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Optic atrophy is present in some patients, particularly in X-linked recessive (CMTX5; 311070) and X-linked dominant (CMTX5; 302800) disease. Juvenile-onset open-angle glaucoma has been reported among members of 2 consanguineous families with type 4B2, or CMT4B2 (604563). The mean age of onset was 8 years.
Charcot-Marie-Tooth disease is a large group of clinically and genetically heterogeneous disorders characterized by progressive motor and sensory polyneuropathy. These can be separated (with overlap) into two large groups on the basis of electrophysiologic criteria: type 1 is the demyelinating form, and type 2 the axonal form. Patients with primarily distal motor neuropathy are sometimes considered to comprise a third type.
Symptoms such as weakness in the extremities and digits have a variable age of onset but usually become evident in late childhood or early adulthood. Small muscles of the hands and feet are often atrophied to some degree. Some patients develop hearing loss of the neurosensory type. Foot deformities such as pes cavus are common. Nerve conduction velocity (reduction) and electromyography can be helpful diagnostically. It may be helpful to look for characteristic changes such as loss of myelinated fibers and focal myelin sheath folding in sural nerve biopsies. Intellectual impairment and dementia are usually not features of Charcot-Marie-Tooth disease.
Hemizygous individuals with X-linked types of CMT such as CMTX2-5 seem to be more likely to have intellectual disabilities, hearing loss, spasticity, and optic neuropathy.
Charcot-Marie-Tooth disease can also be classified on the basis of their hereditary patterns including autosomal dominant, autosomal recessive, X-linked recessive, and X-linked dominant. Each of these contains yet more distinct subtypes as defined by mutations in at least 40 genes.
The wide range of disease severity and the overlapping of many signs can make pedigree construction and the determination of recurrence risks and prognosis challenging. The only recourse may be genotyping.
The widespread and debilitating polyneuropathy requires a multidisciplinary management approach with neurologists, physical and occupational therapists, audiologists, pain specialists, and orthopedists. Pharmaceuticals such as gabapentin may be used for neuropathic pain. Surgery for pes cavus and joint dysplasias can be helpful.
Ocular problems begin by about age 7 years when various degrees of ophthalmoplegia appear. By the second decade damage to the optic nerves is evident (optic atrophy) leading to severe vision loss.
This mitochondrial DNA depletion syndrome allows normal development in the first year of life. By 10-18 months of age, muscle weakness and coordination become evident. Deep tendon reflexes are diminished or absent. The muscle deficits are relentlessly progressive and by teenage years most individuals are wheelchair-bound. Generalized seizures are common. Facial and limb dyskinesia of an athetoid nature is evident to a variable degree. A sensory polyneuropathy develops in many patients. Cerebellar atrophy is evident on neuroimaging.
Neurosensory hearing loss may become evident late in the first decade of life. The amount of hearing loss is progressive, leading eventually to profound deafness. Some patients experience a complete loss of vestibular caloric responses.
Most individuals live to adulthood but a severe form of this disease in which liver damage and encephalopathy occur limits the lifespan to about 5 years.
This infantile-onset form of spinocerebellar atrophy results from homozygous or compound heterozygous mutations in the C10ORF2 gene (10q24) which encodes the so-called Twinkle and Twinky mitochondrial proteins. Since the Twinkle protein is involved in the production and maintenance of mitochondrial DNA, its malfunction leads to reduced quantities of mtDNA in the liver and CNS but not in skeletal muscle.
Mutations in the C10ORF2 gene affecting the Twinkle protein may be responsible for an autosomal dominant progressive ophthalmoplegia (609286) in which ptosis and cataracts are often found but the more extensive muscle and sensory deficits are often missing. This is one of the better examples of seemingly unique, allelic phenotypes resulting from different mutations in the same gene.
No effective treatment has been reported but physical therapy, assistive hearing devices, and low vision aids might be helpful in selected patients.
Nystagmus and optic atrophy are important ocular signs. The visual pathway, both anterior and posterior, is consistently involved and field defects are common even though many patients are asymptomatic. OCT usually shows a reduced nerve fiber layer secondary to loss of axons. About half of patients have abnormal visual evoked potentials. A few patients experience a sudden loss of central vision during the second decade of life.
Friedreich ataxia is a progressive neurodegenerative disorder with onset before puberty. The spinocerebellar tracts, dorsal columns, pyramidal tracts, cerebellum, medulla, and optic radiation, may all be involved. The outstanding symptom is ataxia with prominent involvement of gait and limbs. Muscle weakness, extensor plantar responses, and absent lower limb reflexes are usually present. Dysarthria is usually notable. Sensory signs include impairment of position and vibratory senses. ‘Twitching’ in limbs and digits is often noted and ‘restless leg syndrome’ is common.
Secondary changes include pes cavus, scoliosis, and hammer toe. Cardiac disease is frequently present and heart failure is the most common cause of death. Most patients have hypertrophic cardiomyopathy with characteristic EKG changes and some have subaortic stenosis as part of the hypertrophied myocardium. Diabetes mellitus is present in 20-25%. Some hearing loss occurs in more than 10% of individuals.
Most patients require a wheelchair within 15 years of disease onset and the mean age of death is about 36 years.
Rare patients with a later onset of FRDA retain lower limb deep tendon reflexes.
Homozygous mutations in FXN (9p21.11) are responsible for Friedreich ataxia. The most common DNA abnormality is a GAA trinucleotide repeat expansion in intron 1. The number of repeats in patients is 70 to more than 1000 compared with 5-30 in normal individuals. FXN encodes the mitochondrial protein frataxin.
About 2% of individuals have point mutations in FXN instead of trinucleotide repeats.
Some of the phenotypic variations may be explained by differences in the number of GAA repeats.
Treatment is largely directed at symptoms including speech and physical therapy and mobility assistive devices. Scoliosis may require surgical intervention.
Patients with this disorder have difficulty initiating voluntary ocular movements upon command or when following targets (oculomotor apraxia). Gaze changes are often initiated first by head thrusting, followed by saccadic eye movements. One may test for this by holding the head whereupon the patient is unable to move the eyes. Ocular apraxia is often evident a few years after symptoms of ataxia are noted and may progress to external ophthalmoplegia. Most patients have exaggerated blinking.
The ataxia is cerebellar in origin with onset usually in the first decade of life (mean age of onset 4.3 years. It is associated with peripheral axonal neuropathy and hypoalbuminemia. Gait imbalance is usually the first symptom followed by upper limb dysmetria. Other variable signs include dysarthria, choreiform or athetoid movements, facial grimacing, tongue and limb fasciculations, areflexia, and distal sensory deficits. All symptoms are progressive and ambulation is lost within a decade of onset. Cerebellar atrophy may be seen on MRI and the EMG shows evidence of axonal neuropathy. Mental function is normal in most patients but some have cognitive impairments.
Mutations in the APTX gene (9p21.1) encoding aprataxin are responsible for this autosomal recessive condition.
There is evidence of clinical and genetic heterogeneity. At least two loci are involved, with the mutation at 9p13 causing an earlier onset of disease (first decade), and hypoalbuminemia, while the second one, ataxia with oculomotor apraxia 2 ) at 9q34 causes a disorder of later onset (2nd or third decade) in which oculomotor apraxia is an inconsistent finding. Oculomotor apraxia is more consistently found in the disorder described here. Cogan-type oculomotor apraxia (257550) lacks other neurologic signs.
No specific treatment is available although physical therapy can be helpful.
Pigmentary retinopathy has been noted by 6 months of age. Typical symptoms of retinitis pigmentosa are reported by early childhood. The visual fields are progressively constricted and a ring scotoma can be plotted. Night blindness and visual acuity loss are evident in the first decade of life and progressively worsen leading to severe handicaps by the third. Fundus pigmentation in the midperiphery becomes more prominent and in at least some patients the pattern consists of typical bone spicules. Cellophane maculopathy has been described.
Proprioceptive deficits and areflexia appear in early childhood and ataxia worsens as individuals mature. Scoliosis and general weakness and wasting become prominent manifestations. Sensory neuropathy with loss of vibratory and position sense, astereognosia, and agraphesthesia can become apparent in the first decade of life. Walking is delayed and gait abnormalities are clearly evident by the second decade leading to orthopedic deformities such as scoliosis. Unassisted walking becomes impossible. The intrinsic hand and foot muscles also have mild weakness. Sural nerve biopsy may reveal loss of large myelinated fibers. Hyperintense signals in the posterior spinal columns can be seen on MRI. No anatomic changes have been described in the cerebrum or cerebellum.
This is an autosomal recessive disorder resulting from homozygous mutations in FLVCR1 (1q32.2-q41). This disorder has some clinical similarities to Biemond 1 syndrome but differs in the inheritance pattern and the molecular basis.
No specific treatment is available but physical therapy and low vision aids may improve the quality of life.
Decreased lacrimation is the major ocular feature in this syndrome and it may be sufficiently severe to result in corneal damage. Decreased corneal sensation as part of the generalized neuropathy likely plays a role. Epithelial defects are slow to heal and their chronic presence along with neurotrophic ulcers often leads to corneal thinning. The blink rate is reduced, especially during crises. The lid fissures are abnormally wide contributing further to corneal drying. The pupillary light response time may be prolonged. Miosis follows administration of methacholine chloride. Optic neuropathy with pallor is often present.
Vasomotor instability and sensory neuropathy are among the outstanding signs in familial dysautonomia. Episodic hypertension alternating with hypotension, hyperhidrosis, cyclic vomiting, and skin blotching are common. Deep tendon reflexes are often diminished or absent and there is a general indifference to pain and temperature. The lingual fungiform papillae are missing resulting in taste disturbances. Emotional instability and impaired coordination are frequently seen. Emotional or physical stress can precipitate dysautonomic crises with nausea, vomiting, agitation, tachycardia, and hypertension. Physical growth may be slow and scoliosis is common. Patients are susceptible to self-injury.
Arrested development in the sensory and autonomic nervous systems results in a reduction in nonmyelinated nerve fibers as well as a reduction in small diameter myelinated axons. Sympathetic ganglia are abnormally small in size. There is hypersensitivity to both sympathomimetic and parasympathomimetic drugs.
Hereditary sensory and autonomic neuropathy type III results from mutations in the IKBKAP gene (9q31). It is an autosomal recessive condition.
A brief report describes 4 sibs with a clinical picture similar to familial dysautonomia with a mutation in DST (6p12.1).
No treatment is available for the general disease but therapies are available for specific problems. Good hydration, assisted ventilation during sleep, and liberal use of tear substitutes can be helpful. Lacrimal ointments and lid taping during sleep are advised. Punctal occlusion should be considered in selected cases. Corneal ulcers or slow healing epithelial defects can be treated with a temporary tarsorrhaphy.
Patients with familial dysautonomia are at increased risk of intraoperative cardiorespiratory complications which can be reduced by adequate hydration, reduced use of volatile anesthetic agents, and attention to postoperative ventilation.