Genetically Established Familial Amyloidotic Polyneuropathy from India: Narrating the Diagnostic "Odyssey" and a Mini Review.

CONTEXT: Familial amyloidotic polyneuropathy (FAP) is often misdiagnosed as other neuropathic illnesses. AIM: To highlight the diagnostic "odyssey" in three families of Indian origin with FAP. SETTINGS AND DESIGN: Cross-sectional, hospital-based study. SUBJECTS AND METHODS: Clinical, radiological, and histological features as well as causes for delayed diagnosis were analyzed in genetically confirmed patients with FAP. STATISTICAL ANALYSIS: Descriptive. RESULTS: Age at evaluation ranged from 24 to 42 years and symptom duration from 1 to 10 years. Referral diagnoses included: (i) in patients 1 and 2-familial dysautonomia, Shy-Drager syndrome, and spino-cerebellar ataxia with seizures, (ii) in patient 3-chronic inflammatory demyelinating polyradiculoneuropathy, and (iii) in patient 4-porphyria. In addition, patients 1 and 2 developed leptomeningeal involvement that was mistaken for tubercular meningitis. Reasons for missed diagnosis included: clinician's lack of awareness, not paying sufficient attention to family history, presence of laboratory distractors such as elevated urinary porphyrins, lack of meticulous search for amyloid in the biopsy, and not performing specific stain for amyloid viz. Congo red. Evidence of amyloid in histological studies of nerve and skin supported by genetic variations in transthyretin gene clinched the diagnosis. The variants identified in our cohort included p.Gly73Glu, p.Val71Ala, and p.Val50Met. CONCLUSION: Lack of awareness and meticulous work-up by clinicians and pathologists contributed to delayed diagnosis of FAP. It is important to establish an accurate diagnosis as these patients may be candidates for upcoming therapies.

Hypersomnolence-hyperkinetic movement disorder in a child with compound heterozygous mutation in 4-aminobutyrate aminotransferase (ABAT) gene.

Deficiency of gamma-amino-butyrate aminotransferase (ABAT) is a rare inherited disorder. A six-month-old girl presented with hyper-somnolence, hyperkinetic movements of distal extremities during wakefulness, hypotonia, bi-pyramidal signs, and impaired response to sound and visual stimuli. Brain MRI at five months showed restricted diffusion along the internal capsule and genu of corpus callosum. A follow up MRI at 18months, showed hyperintensities in brainstem, external and internal capsule, 'trilaminated' appearance of posterior limb of internal capsule and dysmyelination of sub-cortical white matter. MRS showed a peak between 2.2ppm and 2.4ppm, corresponding to glutamine, glutamate and GABA. EEG was normal at six months but showed multifocal epileptiform discharges at 18months. Targeted exome sequencing revealed compound heterozygous missense variations in ABAT resulting in its reduced function. We report the novel association of hypersomnolence and hyperkinetic movement disorder with ABAT variations thus expanding the clinical spectrum of this uncommon neuro-metabolic disorder and discuss the emerging role of GABA in pathways regulating sleep-wake cycle and movement disorders.