| Inbound Relationships |
Type |
Active |
Source |
Characteristic |
Refinability |
Group |
| Autosomal recessive spastic paraplegia type 63 (SPG63) is an extremely rare and complex form of hereditary spastic paraplegia characterized by an onset in infancy of spastic paraplegia (presenting with delayed walking and a scissors gait) associated with short stature, and normal cognition. Periventricular deep white matter changes in the corpus callosum are noted on brain imaging. SPG63 is caused by a homozygous mutation in the AMPD2 gene (1p13.3) encoding AMP deaminase 2. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| Autosomal recessive spastic paraplegia type 61 (SPG61) is a rare, complex form of hereditary spastic paraplegia characterized by an onset in infancy of spastic paraplegia (presenting with the inability to walk unsupported and a scissors gait) associated with a motor and sensory polyneuropathy with loss of terminal digits and acropathy. SPG61 is due to a mutation in the ARL6IP1 gene (16p12-p11.2) encoding the ADP-ribosylation factor-like protein 6-interacting protein 1. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| Spastic paraplegia-Paget disease of bone syndrome is an extremely rare, complex form of hereditary spastic paraplegia characterized by a slowly progressive spastic paraplegia (with increased muscle tone, decreased strength in the anterior tibial muscles and hyperreflexia in the lower extremities with Babinski sign) presenting in adulthood, associated with Paget disease of the bone. Cognitive decline, dementia and myopathic changes at muscle biopsy have not been reported. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| Autosomal spastic paraplegia type 18 (SPG18) is a rare, complex type of hereditary spastic paraplegia characterized by progressive spastic paraplegia (presenting in early childhood) associated with delayed motor development, severe intellectual disability and joint contractures. A thin corpus callosum is equally noted on brain magnetic resonance imaging. SPG18 is caused by a mutation in the ERLIN2 gene (8p11.2) encoding the protein, Erlin-2. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| Autosomal recessive spastic paraplegia type 25 (SPG25) is a rare, complex type of hereditary spastic paraplegia characterized by adult-onset spastic paraplegia associated with spinal pain that radiates to the upper or lower limbs and is related to disc herniation (with minor spondylosis), as well as mild sensorimotor neuropathy. The SPG25 phenotype has been mapped to a locus on chromosome 6q23-q24.1. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare, hereditary spastic paraplegia that can present as either a pure or complex phenotype. The pure form is characterized by lower limb spasticity, hyperreflexia and extensor plantar responses, presenting in childhood or adolescence. The complex form is characterized by the association with additional manifestations including peripheral neuropathy with upper limb muscle atrophy, moderate intellectual disability and parkinsonism. Deafness and retinitis pigmentosa have also been reported. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare, pure or complex form of hereditary spastic paraplegia typically characterized by presentation in late adolescence or early adulthood as a pure phenotype of lower limb spasticity with hyperreflexia and extensor plantar responses, as well as mild bladder disturbances and pes cavus. Rarely, it can present as a complex phenotype with additional manifestations including epilepsy, variable peripheral neuropathy and/or memory impairment. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| Spastic paraplegia-precocious puberty syndrome is a complex form of hereditary spastic paraplegia characterized by the onset of progressive spastic paraplegia associated with precocious puberty (due to Leydig cell hyperplasia) in childhood (at the age of 2 years). Moderate intellectual disability was also reported. There have been no further descriptions in the literature since 1983. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
1 |
| A complex form of hereditary spastic paraplegia characterized by a spastic paraplegia presenting in adolescence, associated with the additional manifestations of sensorial hearing impairment due to auditory neuropathy and persistent vomiting due to a hiatal or paraesophageal hernia. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
1 |
| Spastic paraplegia-nephritis-deafness syndrome is a complex form of hereditary spastic paraplegia characterized by progressive, variable spastic paraplegia associated with bilateral sensorineural deafness, intellectual disability, and progressive nephropathy. There have been no further descriptions in the literature since 1988. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
5 |
| A complex hereditary spastic paraplegia characterized by progressive lower limbs weakness and spasticity, upper limbs weakness, dysarthria, hypomimia, sphincter disturbances, peripheral neuropathy, learning difficulties, cognitive impairment and dementia. Magnetic resonance imaging shows thin corpus callosum, cerebral atrophy, and periventricular white matter changes. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A form of hereditary spastic ataxia characterised by an onset usually in adulthood (but ranging from 10-72 years) of progressive bilateral lower limb weakness and spasticity and sometimes predominant cerebellar ataxia. In addition to frequent sphincter dysfunction and decreased vibratory sense at the ankles, manifestations may include optical neuropathy, nystagmus, blepharoptosis, ophthalmoplegia, decreased hearing, scoliosis, pes cavus, motor and sensory neuropathy, muscle atrophy, parkinsonism, and dystonia. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| Macrocephaly-spastic paraplegia-dysmorphism syndrome is a rare syndrome of multiple congenital anomalies characterized by macrocephaly (of post-natal onset) with large anterior fontanelle, progressive complex spastic paraplegia, dysmorphic facial features (broad and high forehead, deeply set eyes, short philtrum with thin upper lip, large mouth and prominent incisors), seizures, and intellectual deficit of varying severity. Inheritance appears to be autosomal recessive. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
6 |
| Spastic paraplegia-glaucoma-intellectual disability syndrome is characterized by progressive spastic paraplegia, glaucoma and intellectual deficit. It has been described in two families. The second described sibship was born to consanguineous parents. The mode of inheritance is autosomal recessive. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare complex hereditary spastic paraplegia characterized by an early onset hypotonia that progresses to spasticity, global developmental delay, severe intellectual disability and speech impairment, microcephaly, short stature and dysmorphic features. Patients often become non-ambulatory, and some develop seizures and stereotypic laughter. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
4 |
| Autosomal recessive spastic paraplegia type 27 is a rare, pure or complex hereditary spastic paraplegia characterized by a variable onset of slowly progressive lower limb spasticity, hyperreflexia and extensor plantar responses, that may be associated with sensorimotor polyneuropathy, decreased vibration sense, lower limb distal muscle wasting, dysarthria and mild to moderate intellectual disability. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| A rare complex hereditary spastic paraplegia characterized by adulthood-onset of slowly progressive, bilateral, mainly lower limb spasticity and distal weakness associated with lower limb pain, hyperreflexia, and reduced vibration sense. Axonal neuropathy is frequently observed on electromyography and nerve conduction examination. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare, pure or complex form of hereditary spastic paraplegia, with variable phenotype, typically characterized by childhood-onset of minimally progressive, bilateral, mainly symmetric lower limb spasticity and weakness, associated with pes cavus, scoliosis, sphincter disturbances and/or urinary bladder hyperactivity. Rare additional associated manifestations may include mild intellectual disability, axonal motor neuropathy, and seizures. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare, complex hereditary spastic paraplegia disorder characterized by infantile onset of progressive lower limb spasticity, global developmental delay, hyperreflexia, clonus and extensor plantar reflexes, associated with dysarthria, intellectual disability, cataracts and hearing impairment. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A type of autosomal recessive pure hereditary spastic paraplegia characterized by infancy onset of crural spastic paraparesis with scissors gait, extensor plantar response, and increased tendon reflexes. Neuroimaging reveals a thin corpus callosum and electromyography and nerve conduction velocity studies are normal. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare autosomal dominant pure hereditary spastic paraplegia characterized by early childhood onset of slowly progressive crural spastic paraparesis presenting with spastic gait, mild stiffness at rest, hyperreflexia (in lower limbs), extensor plantar responses and, in some, mild postural tremor, pes cavus, sphincter disturbances and sensory loss at ankles. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| Autosomal recessive spastic paraplegia type 60 is a rare, complex hereditary spastic paraplegia disorder characterized by infantile onset of progressive lower limb spasticity, inability to walk, hypertonia and impaired vibration sense at ankles, with complicating signs including sensory impairment, nystagmus, motor axonal neuropathy and mild intellectual disability. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare, complex hereditary spastic paraplegia disorder characterized by infantile onset of progressive lower limb spasticity, severe gait disturbances leading to a non-ambulatory state, absent deep tendon reflexes and amyotrophy. Additional signs include severe sensorimotor neuropathy, pes equinovarus and mild intellectual disability. Cerebellar and corpus callosum hypoplasia, as well as colpocephaly, are observed on neuroimaging. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| Autosomal recessive spastic paraplegia type 14 is a rare, complex hereditary spastic paraplegia characterized by adulthood-onset of slowly progressive spastic paraplegia of lower limbs presenting with spastic gait, hyperreflexia, and mild lower limb hypertonicity associated with mild intellectual disability, visual agnosia, short and long-term memory deficiency and mild distal motor neuropathy. Bilateral pes cavus and extensor plantar responses are also associated. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare genetic peripheral neuropathy characterized by early hypotonia evolving to spastic paraparesis, areflexia, decreased pain and temperature sensitivity, autonomic neuropathy, gastroesophageal reflux disease, recurrent pneumonia and respiratory problems. Patients also have intellectual disability and dysmorphic features, including mild brachycephalic microcephaly, short broad neck, low anterior hairline and coarse face. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
6 |
| A complex hereditary spastic paraplegia characterised by mild to severe lower limb spasticity, hyperreflexia, extensor plantar responses, impaired vibration sensation, pes cavus, and significant wasting and weakness of the small hand muscles. Temporal lobe epilepsy and cognitive dysfunction have been also reported. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A complex, hereditary, spastic paraplegia characterized by delayed motor development, spasticity, and inability to walk, later progressing to quadriplegia, motor aphasia, bowel and bladder dysfunction. Patients also present with vision problems and mild intellectual disability. The disease affects only males. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare, pure or complex form of hereditary spastic paraplegia characterized by progressive spastic paraplegia with pyramidal signs in the upper and lower limbs, and decreased vibration sense. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare form of hereditary spastic paraplegia characterized by delayed walking, toe walking, unsteady and spastic gait, hyperreflexia of the lower limbs, and extensor plantar responses. Upper limbs spasticity and dystonia, subclinical axonal neuropathy, cognitive impairment and intellectual disability have also been associated. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A very rare, pure form of spastic paraplegia characterized by an onset in infancy of lower limb spasticity associated with gait disturbances, scissor gait, tiptoe walking, clonus and increased deep tendon reflexes. Mild upper limb involvement may occasionally also be associated. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| X-linked complex hereditary spastic paraplegia |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| X-linked pure hereditary spastic paraplegia |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare genetic neurological disorder characterized by postnatal microcephaly, hypotonia during infancy followed in most cases by progressive spasticity mainly affecting the lower limbs, and spastic diplegia or paraplegia, intellectual disability, delayed or absent speech, and dysarthria. Seizures and mildly dysmorphic features have been described in some patients. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
6 |
| A rare autosomal recessive complex spastic paraplegia characterized by mostly adult-onset progressive spasticity and weakness predominantly affecting the lower limbs, axonal motor and sensory neuropathy, and cerebellar symptoms like ataxia, dysarthria, and oculomotor abnormalities. Variable degrees of cognitive impairment may also be present. Subtle extrapyramidal involvement and supranuclear gaze palsy were reported in some cases. Features on brain imaging include cerebral and cerebellar atrophy and sometimes abnormalities of the corpus callosum or basal ganglia. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare genetic neurological disorder characterized by progressive spastic paraparesis and delayed gross motor development with an onset in infancy or early childhood. Patients also show variable degrees of intellectual disability, speech delay, and dysarthria. Other reported features include microcephaly, seizures, bifid uvula with or without cleft palate, and ocular anomalies. Brain imaging shows white matter abnormalities in the periventricular and other regions. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
4 |
| A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay and intellectual disability, progressive spondyloepimetaphyseal dysplasia, short stature, short fourth metatarsals, and dysmorphic craniofacial features (including microcephaly, hypertelorism, epicanthal folds, mild ptosis, strabismus, malar hypoplasia, short nose, depressed nasal bridge, full lips, small, low-set ears, and short neck). Craniosynostosis, generalized hypotonia, as well as asymmetry of the cerebral hemispheres and mild thinning of the corpus callosum on brain imaging have also been described. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
5 |
| Intellectual disability-spasticity-ectrodactyly syndrome is a rare intellectual disability syndrome characterized by severe intellectual disability, spastic paraplegia (with wasting of the lower limbs) and distal transverse defects of the limbs (e.g. ectrodactyly, syndactyly, clinodactyly of the hands and/or feet). |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare complex hereditary spastic paraplegia characterized by juvenile to adult onset of slowly progressive spasticity mainly affecting the lower limbs, associated with spastic dysarthria and motor neuropathy. Additional manifestations include congenital bilateral cataract, gastroesophageal reflux, persistent vomiting, mild cerebellar signs, pes cavus, and occasionally short stature, among others. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| A rare predominantly pure hereditary spastic paraplegia characterized by juvenile or adult onset of slowly progressive spastic paraparesis, gait disturbances, and increased tendon reflexes. Additional variable manifestations include pes cavus, dysarthria, sensory impairment, and urinary symptoms. Cognition is normal. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| A rare complex hereditary spastic paraplegia characterized by early onset of slowly progressive spastic para- or tetraparesis, increased tendon reflexes, positive Babinski sign, global developmental delay, cognitive impairment, and pseudobulbar palsy. Additional manifestations include dysmorphic facial features, tremor, short stature, and urinary incontinence. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| A pure form of hereditary spastic paraplegia characterized by adult onset of crural spastic paraparesis, hyperreflexia, extensor plantar responses, proximal muscle weakness, mild muscle atrophy, decreased vibration sensation at ankles, and mild urinary dysfunction. Foot deformities have been reported to eventually occur in some patients. No abnormalities are noted on brain magnetic resonance imaging and peripheral nerve conduction velocity studies. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| A rare, complex hereditary spastic paraplegia characterized by an early onset and slow progression of spastic paraplegia associated with cerebellar signs, nystagmus, peripheral neuropathy, extensor plantar responses and borderline to mild intellectual disability. Additional features of hypo- or areflexia, mild upper limb involvement and significant visual impairment (optic atrophy, vision loss, astigmatism) have been reported. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| Autosomal recessive spastic paraplegia type 77 is a rare, pure or complex hereditary spastic paraplegia characterized by an infancy to childhood onset of slowly progressive lower limb spasticity, delayed motor milestones, gait disturbances, hyperreflexia and various muscle abnormalities, including weakness, hypotonia, intention tremor and amyotrophy. Ocular abnormalities (e.g. strabismus, ptosis) and other neurological abnormalities, such as dysarthria, seizures and extensor plantar responses, may also be associated. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| Childhood onset nemaline myopathy, or mild nemaline myopathy is a type of nemaline myopathy characterized by distal muscle weakness, and sometimes slowness of muscle contraction. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| Intermediate nemaline myopathy |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| An autosomal dominant hereditary neurodegenerative disease with characteristics of progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Associated with mutations in the superoxide dismutase-1 gene (SOD1) on chromosome 21q22. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| An autosomal recessive hereditary neurodegenerative disease with characteristics of progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Associated with mutations in the superoxide dismutase-1 gene (SOD1) on chromosome 21q22. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| A rare genetic bone disease characterized by short stature, bilateral congenital hip dislocation, radial head dislocation, carpal coalition, scoliosis, pes cavus, and atlantoaxial subluxation. Dysmorphic facial features include broad forehead, broad nasal bridge, hypertelorism, and mild midface hypoplasia. Association with bilateral sensorineural hearing loss has also been described. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
6 |
| A rare genetic neuromuscular disease characterized by late onset of mild, progressive, proximal muscle weakness, severe myalgias during and after exercise, and susceptibility to rhabdomyolysis. Intellectual disability is mild or absent. There are no abnormalities of the skin. Muscle biopsy shows focal depletion of mitochondria especially at the center of muscle fibers, surrounded by enlarged mitochondria at the periphery. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
1 |
| A neurodegenerative disease with characteristics of progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Associated with mutations in the superoxide dismutase-1 gene (SOD1) on chromosome 21q22. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| A very rare severe motor neuron disease with manifestation of progressive upper and lower motor neuron degeneration causing facial spasticity, dysarthria, and gait disorders with onset before 25 years of age. Caused by homozygous mutation in the gene encoding alsin ALS2 (2q33-q35). |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
1 |
| Juvenile amyotrophic lateral sclerosis (JALS) is a very rare severe motor neuron disease characterized by progressive upper and lower motor neuron degeneration causing facial spasticity, dysarthria, and gait disorders with onset before 25 years of age. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| A neurodegenerative disease with characteristics of progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Associated with the ALS3 gene on the cytogenetic location 18q21. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
1 |
| A very rare severe motor neuron disease with manifestation of progressive upper and lower motor neuron degeneration causing facial spasticity, dysarthria, and gait disorders with onset before 25 years of age. There is evidence this disease is caused by homozygous or compound heterozygous mutation in the spatacsin gene (SPG11) on chromosome 15q21. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
1 |
| A neurodegenerative disease with characteristics of progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Caused by heterozygous mutation in the FUS gene on chromosome 16p11. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| A neurodegenerative disease with characteristics of progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Cytogenetic location is 20p13. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| A neurodegenerative disease with characteristics of progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Caused by heterozygous mutation in the VAPB gene on chromosome 20q13. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| A neurodegenerative disease with characteristics of progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Caused by heterozygous mutation in the angiogenin gene (ANG) on chromosome 14q11. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| A rare multiple congenital anomalies/dysmorphic syndrome characterized by profound intellectual disability, choreoathetosis, progressive spastic diplegia, progressive tapetoretinal degeneration with loss of retinal vessels, and glomerulopathy resulting in death late in the first or early in the second decade of life. Absence of the cerebellar granular layer has been reported. There have been no further descriptions in the literature since 1982. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
4 |
| A neurodegenerative disease with characteristics of progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. There is evidence this disease is caused by heterozygous mutation in the TARDBP gene that encodes the TDP43 protein on chromosome 1p36. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| Familial infantile bilateral striatal necrosis is the familial form of infantile bilateral striatal necrosis, a syndrome of bilateral symmetric spongy degeneration of the caudate nucleus, putamen and globus pallidus characterized by developmental regression, choreoathetosis and dystonia progressing to spastic quadriparesis. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare genetic neurological disorder characterized by postnatal onset of severe global developmental delay, profound mental retardation, progressive microcephaly, progressive spasticity evolving into spastic quadriplegia with joint contractures, generalized seizures, and irritability. Severe choreoathetosis and dysmorphic features are absent. Brain imaging shows progressive cerebellar atrophy followed by cerebral atrophy affecting both white and gray matter, but no pontine involvement. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
4 |
| A rare, autosomal dominant cerebellar ataxia characterized by pure and slowly progressive cerebellar signs combining gait instability, dysarthria, nystagmus, saccadic eye movements and diplopia. Less frequent clinical signs and symptoms include spasticity, hyperreflexia, decreased distal vibration sense, urinary urgency or incontinence and postural tremor. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| Spinocerebellar ataxia type 41 is a rare autosomal dominant cerebellar ataxia type III disorder characterized by adult-onset progressive imbalance and loss of coordination associated with an ataxic gait. Mild atrophy of the cerebellar vermis has been reported on brain magnetic resonance imaging. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| Spinocerebellar ataxia type 43 is a rare autosomal dominant cerebellar ataxia type I disorder characterized by late adult-onset of slowly progressive cerebellar ataxia, typically presenting with balance and gait disturbances, in association with axonal peripheral neuropathy resulting in reduced/absent deep tendon reflexes and sensory impairment. Lower limb pain and amyotrophy may be present, as well as various cerebellar signs, including dysarthria, nystagmus, hypometric saccades and tremor. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare, severe, genetic, neurometabolic disease characterized by infantile-onset of progressive neurodevelopmental regression, optic atrophy with nystagmus and diffuse white matter disease. Affected individuals usually have central hypotonia that progresses to limb spasticity and hyperreflexia, eventually resulting in a vegetative state. Recurrent chest infections are frequently associated and seizures (usually generalized tonic-clonic) may occasionally be observed. Brain magnetic resonance imaging shows diffuse bilateral symmetric abnormalities in the cerebral periventricular white matter, with variable lesions in other areas but sparing the basal ganglia. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
4 |
| A rare, genetic, neurometabolic disease characterized by early onset encephalopathy with progressive microcephaly, severe global development delay, seizures, hypotonia, feeding difficulties, variable cardiac abnormalities, and cataracts. Brain MRI shows distinct pattern with high T2 signal and restricted diffusion in the posterior limb of the internal capsule in combination with delayed myelination and progressive cerebral atrophy. The disease is typically fatal. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| Toxic maculopathy due to antimalarial drugs is a rare, acquired eye disease, due to long-term exposure to chloroquine (CQ) or hydroxychloroquine (HCQ), characterized by a slowly progressive, usually non-reversible, development of bilateral atrophic bull's-eye maculopathy (progressive loss of central vision acuity, reduced color vision and central scotoma), which in severe cases can spread over the entire fundus, leading to widespread retinal atrophy and visual loss. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| Odontoleukodystrophy (disorder) |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
4 |
| Hypomyelination, hypogonadotropic hypogonadism, hypodontia syndrome (disorder) |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
4 |
| A rare, genetic, neurological disorder characterized by childhood to adolescent onset of progressive myoclonus (which becomes very severe and results in major motor impediment) associated with infrequent tonic-clonic seizures, and, occasionally, ataxia. Learning disability prior to seizure onset and mild cognitive decline may be associated. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
1 |
| Progressive congenital rubella encephalomyelitis |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare primary bone dysplasia with increased bone density characterized by slowly progressive endosteal hyperostosis and osteosclerosis exclusively of the skull base and the calvaria, resulting in entrapment and dysfunction of cranial nerves I, II, V, VII, and VIII. First symptoms often appear during the second decade of life and include disturbances in smell, vision, facial sensation and expression, hearing, and balance, as well as headaches due to increased ocular and intracranial pressure. After the fourth decade, radiological progression is minimal, although decreased intracranial volume can lead to death in severe cases. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
5 |
| A rare genetic muscular dystrophy characterized by progressive muscle weakness in a scapulo-humero-peroneal and distal distribution, featuring wrist extensor weakness, finger and foot drop, scapular winging, mild facial weakness, contractures of the Achilles tendon, elbow, and shoulder, and diminished or absent deep tendon reflexes. A predilection for the upper extremities has been reported in some patients. Respiratory muscles are spared until late in the disease course. Age of onset, progression, and severity of the disease vary significantly between individuals. Muscle biopsy shows groups of atrophic type I fibers and increased internal nuclei. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| A rare autosomal recessive cerebellar ataxia characterized by onset of dystonia and other extrapyramidal signs, ataxia, oculomotor apraxia, and progressive sensorimotor polyneuropathy in the first decade of life. Patients present distal muscle weakness and atrophy, decreased vibratory sensation, and areflexia, and usually become wheelchair-bound by the third decade. Variable cognitive impairment may also be seen. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
1 |
| A rare genetic neurological disorder characterized by infantile onset of progressive leukoencephalopathy, microcephaly, severe global developmental delay, and spasticity resulting in quadriparesis and posture deformation. Additional features include an abnormally exaggerated startle reflex, seizures, dystonia, and hypomimia or amimia, as well as progressive chest deformities and contractures of large and hyperextensibility of small joints, among others. Thin corpus callosum is a prominent feature in brain imaging, in addition to white matter abnormalities consistent with leukoencephalopathy. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| A rare developmental defect with connective tissue involvement characterized by joint hyperextensibility and multiple dislocations of large joints, severe myopia, and short stature. Other common features include retinal detachment, iris and chorioretinal coloboma, kyphoscoliosis and other spine deformities, pectus carinatum, talipes equinovarus, and progressive hearing loss. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
5 |
| A rare leukodystrophy characterized by a spectrum of progressive neurologic manifestations comprising rapidly progressive early-onset nystagmus, spastic tetraplegia, and visual and hearing impairment, resulting in death in early childhood, as well as later onset of slowly progressive complex spastic ataxia with pyramidal and cerebellar symptoms and loss of developmental milestones. Brain imaging shows diffuse hypomyelination of the subcortical and deep white matter, cerebellar atrophy, and diffuse spinal cord volume loss. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
4 |
| A rare mitochondrial oxidative phosphorylation disorder due to nuclear DNA anomalies characterized by onset of slowly progressive proximal lower limb weakness and exercise intolerance in the first decade of life, followed by weakness of neck flexor, shoulder, and distal leg muscles. Facial muscles become involved still later in the disease course. Additional manifestations are restrictive pulmonary function and short stature. Laboratory studies reveal lactic acidemia and increased serum creatine kinase. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
1 |
| A rare genetic neurological disorder characterized by pediatric onset of calcifying leukoencephalopathy and skeletal dysplasia. Reported structural brain abnormalities include agenesis of corpus callosum, ventriculomegaly, congenital hydrocephalus, pontocerebellar hypoplasia, periventricular calcifications, Dandy-Walker malformation and absence of microglia. Characteristic skeletal features include increased bone mineral density (reported in skull, pelvic bone and vertebrae), platyspondyly, and under-modeling of tubular bones with widened/radiolucent metaphysis and constricted/sclerotic diaphysis. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
4 |
| A rare, genetic, autosomal recessive axonal hereditary motor and sensory neuropathy disease characterized by prenatal onset of a severe sensorimotor axonal polyneuropathy (reflected by reduced fetal movement and polyhydramnios), manifesting, at birth, with respiratory failure requiring mechanical ventilation, profound muscular hypotonia, rapidly progressing distal muscle weakness, and absent deep tendon reflexes, in the absence of contractures, leading to death before 8 months of age. Neuropathological findings show severe loss of large- and medium-sized myelinated fibers without signs of demyelination. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
1 |
| A rare glycogen storage disease characterized by slowly progressive myopathy with storage of polyglucosan in muscle fibers. Age of onset ranges from childhood to late adulthood. Patients present proximal or proximodistal weakness predominantly of limb-girdle muscles. Variable features include exercise intolerance or myalgia. Serum creatine kinase is normal or mildly elevated. There is usually no overt cardiac involvement. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| A rare, genetic, neurological disorder characterized by childhood-onset severe myoclonic and tonic-clonic seizures and early-onset ataxia leading to severe gait disturbances associated with normal to slightly diminished cognition. Scoliosis, diffuse muscle atrophy and subcutaneous fat loss, as well as developmental delay, may be associated. Brain MRI may reveal complete agenesis of the corpus callosum, ventriculomegaly, interhemispheric cysts, and simplified gyration (frontally). |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
1 |
| A rare spondyloepiphyseal dysplasia characterized by progressive joint contractures with premature degenerative joint disease, particularly in the knee, hip, and finger joints. Patients are of normal height and present with gait problems, joint pain, and enlarged joints with joint restriction and contractures. Radiological features include generalized platyspondyly, hypoplastic ilia, epiphyseal flattening with metaphyseal splaying of the tubular bones, and broad, elongated femoral necks with marked coxa valga. Histopathologic examination of cartilage shows PAS-positive cytoplasmic inclusion bodies in chondrocytes. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
5 |
| A rare developmental defect during embryogenesis caused by homozygous mutations in the PCNA gene and characterized by neurodegeneration, postnatal growth retardation, prelingual sensorineural hearing loss, premature aging, ocular and cutaneous telangiectasia, learning difficulties, photophobia, and photosensitivity with evidence of predisposition to sun-induced malignancy. Progressive neurologic deterioration leads to gait disturbances, muscle weakness, speech and swallowing difficulties and progressive cognitive decline. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare, genetic interstitial lung disease characterised by accumulation of lipoproteins in the pulmonary alveoli leading to restrictive lung disease and respiratory failure. Patients present with dyspnoea, tachypnoea, cough, failure to thrive, and digital clubbing. Liver disease have been described in some cases including hepatomegaly, steatosis, fibrosis or cirrhosis. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| A rare, systemic amyloidosis characterized by slowly progressive renal disease presenting with proteinuria, hypertension and decreased glomerular filtration rate leading to progressive renal failure. Histology reveals amyloid deposits of leukocyte chemotactic factor-2 protein in the renal cortical interstitium, tubular basement membranes, glomeruli and the vessel walls. Extra-renal deposits can be seen in the liver, lungs, spleen and adrenal glands. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| A rare neurologic disease characterized by multifaceted motor system dysfunctions and cognitive defects such as asymmetric rigidity, bradykinesia, limb apraxia, and visuospatial dysfunction. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
4 |
| A rare genetic, skeletal muscle disease with characteristics of early-onset hypotonia, muscle weakness, global developmental delay with intellectual disability and cardiomyopathy. Congenital structural heart defects and ichthyosiform cutaneous lesions have also been associated. Muscle biopsy shows characteristic enlarged mitochondria located at the periphery of muscle fibres. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
4 |
| A rare autosomal dominant distal hereditary motor neuropathy characterized by onset of slowly progressive distal limb weakness and atrophy between the second and fifth decades of life. Sensory involvement is typically less pronounced or absent. The severity of the condition is variable, and both lower and upper extremities may be involved. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
1 |
| Goldmann-Favre syndrome (GFS) is a vitreoretinal dystrophy characterized by early onset of night blindness, reduced bilateral visual acuity, and typical fundus findings (progressive pigmentary degenerative changes, macular edema, retinoschisis). |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare, slowly progressive form of systemic mastocytosis (SM) characterized by gradual accumulation of neoplastic mast cells in the visceral organs. Patients typically present with splenomegaly, hypercellular marrow and, in most cases, urticaria pigmentosa-like skin lesions. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| Limb-girdle muscular dystrophy due to POMK deficiency is a form of limb-girdle muscular dystrophy presenting in infancy with muscle weakness and delayed motor development (eventually learning to walk at 18 months of age) followed by progressive proximal weakness, pseudohypertrophy of calf muscles, mild facial weakness, and borderline intelligence. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare slowly progressive autosomal recessive syndromic cerebellar ataxia characterized by late-onset cerebellar dysfunction (including gait and limb ataxia, nystagmus, and dysarthria), bilateral vestibulopathy (abnormal vestibulo-ocular reflex), and axonal sensory neuropathy. Variable features may include chronic cough and autonomic dysfunction. Brain imaging usually shows cerebellar atrophy. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| Progressive macular hypomelanosis |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| A rare genetic multiple congenital anomalies/dysmorphic syndrome with characteristics of slowly progressive night blindness, skeletal abnormalities (sloping shoulders, joint hyperextensibility, minor radiological anomalies) and characteristic facial features (periorbital anomalies, malar flatness, retrognathia). Additional manifestations include myopia and extinguished electroretinograms. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
3 |
| A rare genetic disease characterized by severe progressive sensorineural hearing loss and progressive cerebellar signs including gait ataxia, action tremor, dysmetria, dysdiadochokinesis, dysarthria, and nystagmus. Absence of deep tendon reflexes has also been reported. Age of onset is between infancy and adolescence. Brain imaging may show variable cerebellar atrophy in some patients. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| PYCR2-related microcephaly-progressive leukoencephalopathy is a rare, genetic, syndromic intellectual disability disorder characterized by progressive postnatal microcephaly, cerebral hypomyelination and severe psychomotor developmental delayed with absent speech, as well as axial hypotonia, appendicular hypertonia with hyperextensibility of the wrists and ankles, hyperreflexia, severe muscle wasting and failure to thrive. Associated craniofacial dysmorphism includes triangular facies with bitemporal narrowing, down- or upslanting palpebral fissures, malar hypoplasia, large malformed ears with overfolded helices, upturned bulbous nose, long smooth philtrum and thin vermilion borders. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
5 |
| A rare primary bone dysplasia characterized by osteosclerosis localized predominantly to the metaphyses and epiphyseal margins of the appendicular bones and metaphyseal equivalents of the axial bones, as well as the vertebral endplates, costal ends, and margins of the flat bones. The skull is usually unaffected. The condition is associated with developmental delay and hypotonia. Seizures and spastic paraplegia have also been reported. Serum alkaline phosphatase and urinary pyridinoline and deoxypyridinoline levels may be elevated. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
| A rare autosomal recessive cerebellar ataxia characterized by early onset of slowly progressive cerebellar atrophy, clinically manifesting with extremity and truncal ataxia, global developmental delay, intellectual impairment, nystagmus, dysarthria, intention tremor, and pyramidal signs, among others. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
4 |
| A rare progressive autosomal dominant macular dystrophy, presenting between the third and sixth decades of life, with characteristics of retinal atrophy and retinal detachment leading to loss of central vision, then peripheral vision, and eventually blindness. |
Clinical course |
True |
Progressive |
Inferred relationship |
Some |
2 |
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