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At a glance

A genetic disorder resulting in familial branchial myoclonus, spastic paraparesis, and cerebellar ataxia.

Incidence

Less than 30 cases have been reported. The original description in 1988 was of a family with six affected individuals in two generations.

Genetic inheritance

Autosomal dominant.

Pathophysiology

The precise mechanism leading to this progressive degenerative condition remains poorly understood. The level of the serotonin metabolite 5-hydroxyindoleacetic acid in the cerebrospinal fluid (CSF) is low, and an abnormality in serotonin-mediated neurotransmission has been proposed as a possible cause.

Diagnosis

Made by clinical features consistent with the syndrome. CT and MRI scans demonstrate severe atrophy of medulla, brainstem and spinal cord, and milder atrophy of the cerebral cortex and cerebellar hemispheres, and vermis with normal pons. The olives have been described as normal in some patients, whereas in others they were enlarged with abnormal signal intensity in the MRI. Ventricular dilatation, atrophy of the corpus callosum and calcifications of the basal ganglia are additional potential findings. CSF studies may reveal a markedly reduced concentration in the serotonin metabolite 5-hydroxyindoleacetic acid. Visual, auditory, and somatosensory evoked responses as well as electroencephalo- and electromyogram are normal. A brain biopsy may reveal demyelination and Rosenthal fibers. These are corkscrew- or worm-like, round or fusiform, eosinophilic, intracytoplasmic, hyaline inclusions in astrocytes that contain high amounts of glial fibrillary acidic protein (GFAP). They are typical for, but not restricted to Alexander Disease. They can also be detected in connection with other neurological disorders with longstanding reactive gliosis (eg, intramedullary ependymomas associated with syringomyelia, astrocytoma, encephalomalacia, prolonged sepsis, malnutrition, and intravenous hyperalimentation). A muscle biopsy may demonstrate grossly abnormal changes of denervation atrophy with evidence of collateral reinnervation.

Clinical aspects

The age at onset is typically between 30 and 50 years. The condition is slowly progressive, leading to severe disability, and death within 5 to 10 years after onset of symptoms. The onset is often insidious and may present with episodes of patchy numbness of the upper body, clumsiness, dysarthria, increasing frequency of choking episodes or leg weakness leading to gait anomalies and requiring increasing support to walk. The cognitive functions remain intact throughout the disease process. Disease progression may manifest as bulbar palsy and rhythmic or dysrhythmic branchial myoclonus (with a frequency of around 1-3 Hz) affecting the palate, pharynx, larynx, but synchronous muscle contractions may also involve the eyes, face, neck, diaphragm, and limbs. Clinical signs are palatal myoclonus, tongue and facial fasciculations, nystagmus, dysphagia, dysphonia, hoarseness, stridor, choking spells, and episodes of asphyxia. Spastic para- or quadriparesis (with preserved, brisk reflexes, and normal sensation), (truncal) cerebellar ataxia, and nystagmus are common at later stages. Transient episodes of atonia may be precipitated by minor triggers such as sneezing, laughter or intense emotion and are considered suggestive ...

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