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Título

PNKP mutation in brothers: One syndrome, two phenotypes

RESUMO

CASE PRESENTATION: Two brothers attend at our clinical practice with dysarthria, gait ataxia, polyneuropathy and oculomotor apraxia. The older one, now with 40 years old, began at the age of 1 year with gait ataxia, seizures and neuropsychomotor developmental delay, at 18 years old was restricted to wheelchair and, actually has severe dysarthria, fragmented saccades, ocular apraxia and severe muscular atrophy and anesthesia and loss of vibratory sensation in legs and arms, totalizing 40 at SARA score. The younger one is 21 years old and had history of falls during childhood, but only with 16 years old the gait ataxia was evident and, currently, walks with strong support due to intense postural instability, associated with ocular apraxia, mild dysarthria, mild symmetric atrophy of hands muscles and also with compromise of tactile and vibratory sensory in legs and arms. Both had cerebellar atrophy seen in neuroimaging, nerve conduction study with severe sensorimotor axonal and demyelinating polyneuropathy, elevated alfa-fetoprotein and dyslipidemia. The patients underwent exome evaluation and missense mutation of PNKP gene in homozygosis was identified and both were diagnosed with Ataxia-oculomotor apraxia type 4.
DISCUSSION: First described in 2015, ataxia-oculomotor apraxia due to PNKP mutation was identified in 11 patients of 8 unrelated Portuguese families. Classified as hereditary autosomal-recessive cerebellar ataxia, this is a rare neurodegenerative disorder and, at the same time, is the second most frequent cause for recessive ataxia in Portugal. In literature review of ataxia-oculomotor apraxia 4 cases, we can find that almost all patients have cerebellar atrophy in brain MRI. The PNKP gene has a important role in DNA-oxidative damage repair and its mutation is associated with Ataxia-oculomotor apraxia type 4, Charcot-Marie-Tooth disease type 2B2 and Microcephaly, seizures, and developmental delay
FINAL COMMENTS: PNPK gene-related ataxia-oculomotor apraxia has a wide spectrum of the age of onset of symptoms, and its diagnosis can only be made with a genetic test, which implies a barrier due to the cost of the test. Although rare, it should be among the possible etiologies in ataxia-oculomotor syndromes.

Palavras Chave

PNKP mutation, Ataxia-oculomotor apraxia 4, hereditary autosomal-recessive cerebellar ataxia