Hereditary Movement Disorders

Hereditary movement disorders encompass the general clinical findings of ataxia (which can be a symptom of over 300 different disorders), dystonia, and chorea. These symptoms, and others, are caused by abnormal neurotransmission in the frontal lobe, basal ganglia, cerebellum, and/or sensory/motor pathways.

• Spinocerebellar Ataxia (SCA) is typically an autosomal dominant disorder characterized by gait disturbance, stance or limb incoordination, and dysarthria. Oculomotor disorders, spasticity, peripheral neuropathy, and swallowing problems may or may not be present.^1,2 On electrophysiological/pathological examination, SCAs can exhibit normal to slowed motor nerve conduction velocities (NCVs) and degeneration of the cerebellum.^1,3 Several types of SCAs have been identified and can be diagnosed with available DNA tests: SCA1, 2, 3/MJD, 6, 7, 8, 10 and 17. Because of overlapping symptoms, the SCAs are difficult to diagnose clinically.³³
  
• DRPLA - (Dentatorubral-Pallidoluysian Atrophy, also known as Haw River Syndrome, Naito-Oyanagi Disease) - DRPLA is a progressive disorder of ataxia, choreoathetosis, and dementia or character changes in adults, and of ataxia, myoclonus, epilepsy and progressive intellectual deterioration in children. The age of onset is from 1-62 years with a mean age of onset of 30 years.
  The diagnosis of DRPLA rests on positive family history, characteristic clinical findings, and the detection of an expansion of a CAG/polyglutamine tract in the DRPLA gene (chromosome 12). The CAG repeat length in patients with DRPLA ranges from 49 to 79. DNA-based testing is 100% sensitive and is widely available.
  DRPLA is inherited in an autosomal dominant manner. Offspring of an individual with a mutant allele have a 50% chance of inheriting the disease-causing allele. DRPLA exhibits significant anticipation, which is 28 years/generation with paternal transmission and 15 years/generation with maternal transmission. Prenatal testing by direct DNA testing is available for fetuses at 50% risk.
  
• Friedreich Ataxia (FA) is an autosomal recessive disorder characterized by gait ataxia, dysarthria, areflexia, sensory loss, and cardiomyopathy.^2,4 On electrophysiological examination, the disorder may appear as an axonal sensory neuropathy.³³ FA is caused by a GAA triplet expansion of the X25 gene on chromosome 9, leading to the production of an abnormal frataxin protein.⁴ FA may be misdiagnosed as hereditary motor-sensory neuropathy or vitamin E deficiency.³³
  
• Refsum Disease is a metabolic, autosomal recessive disorder characterized by night blindness, distal weakness, and gait ataxia.^5,6 Upon electrophysiological/ pathological examination, patients with Refsum disease may exhibit axonal loss, slowed motor and sensory nerve conduction velocities, and in some cases, cerebellar degeneration.^3,6 Elevated levels of phytanic acid in blood or plasma are found in nearly every case of Refsum disease, but are not pathognomonic to the disease.⁵ The differential diagnosis includes, but is not limited to, Friedreich ataxia, multiple sclerosis, Amyotrophic Lateral Sclerosis (ALS) and Charcot-Marie-Tooth (CMT) disease.⁶
  
• Adrenoleukodystrophy (ALD) is a pediatric, metabolic, X-linked recessive disorder characterized by hyperactivity and inattention in the beginning phases of the disorder.⁷ Other clinical features of ALD include spastic paraparesis, dysphagia, dysarthria, visual loss, hearing loss, and adrenal insufficiency.^7,8 Electrophysiological examination may show normal or slowed motor and sensory nerve conduction velocities.³ Abnormally high levels of very long chain fatty acids (VLCFAs) are detected in individuals with ALD.⁸ ALD may present similar to metachromatic leukodystrophy and Addison disease.⁷
  
• Adrenomyeloneuropathy (AMN) is the adult form of ALD with clinical features of slowly progressive distal weakness, adrenal dysfunction, hypogonadism, and spasticity.⁸ Behavioral disturbances, dementia, and seizures often present as well.⁷ AMN can be misdiagnosed as chronic multiple sclerosis.⁷
  
• Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) is a mitochondrial, maternally inherited disorder characterized by ataxia, axonal sensory neuropathy, retinal degeneration, pyramidal signs, mental deterioration, and proximal weakness.⁹ A point mutation at the 8,993rd base pair in the ATPase 6 gene of mitochondrial DNA (mtDNA) is diagnostic of NARP.¹⁰ NARP may appear similar to Dejerine-Sottas disease, Friedreich ataxia, Multiple Sclerosis, Charcot-Marie-Tooth (CMT), or Amyotrophic Lateral Sclerosis (ALS).⁶
  
• Leber hereditary optic neuropathy (LHON) is a mitochondrial, maternally inherited disorder affecting adolescents and young adults.⁹ It is characterized by painless, acute and subacute visual loss, and subsequent optic atrophy.¹⁰ Various mtDNA point mutations to ND1, ND2, ND4, ND5, ND6, or cytochrome b genes are diagnostic of LHON.¹⁰
  
• Huntington Disease (HD) is an autosomal dominant disorder characterized by chorea, dementia, and psychiatric symptoms.¹¹ CT and MRI may demonstrate atrophy of the caudate nucleus and PET scan may demonstrate hypometabolism of glucose in the striatum.²⁷ Expanded CAG trinucleotide repeats of the IT15 gene on chromosome 4 are diagnostic of HD.²⁷ HD may present similar to Dentatorubral-Pallidoluysian Atrophy (DRPLA), benign hereditary chorea, cerebrovascular diseases, neuroacanthocytosis, tardive dyskinesia with psychiatric symptomatology, Sydenham's chorea, Creutzfeldt-Jakob disease, or familial Alzheimer's disease with myoclonus.^11,12
  
• Idiopathic Torsion Dystonia (ITD, also known as dystonia musculorum deformans or early-onset torsion dystonia) is an autosomal dominant disorder with reduced penetrance (30-40%) characterized by abnormal limb movements that progress throughout the body.¹³ Imaging studies have not been helpful in diagnosing this disorder.²⁷ Electrophysiological examination may show tonic co-contraction of antagonistic muscles as a result of decreased activation of group 1a inhibitory interneurons in the brainstem and spinal cord.²⁷ A deletion of the GAG triplet repeat in the torsinA gene (DYT1) on chromosome 9 is diagnostic of ITD.¹³ ITD may present similar to Wilson disease, writer's cramp, or dystonic reactions from adverse drug effects to certain medications.¹⁴

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