Homozygous PNPLA6 Mutation (p.Arg1183Trp) Associated With Isolated Cerebellar Ataxia: A Familial Case Report.

This case report describes a novel presentation of homozygous PNPLA6 gene mutation (c.3547C>T; p.Arg1183Trp) manifesting as isolated cerebellar ataxia in two male first cousins from an Emirati family, characterized by cerebellar ataxia without systemic manifestation. This report highlights the implications for genetic diagnosis and counseling in families with consanguinity. Two affected male first cousins (ages 53 and 61 years) were retrospectively identified through our tertiary-care neurology clinic's medical registry. Both patients underwent standardized neurological examination, brain magnetic resonance imaging (MRI), and next-generation sequencing of ataxia-related genes. The family history was assessed in consenting relatives. Both patients presented with insidious onset dysarthria, progressive truncal and limb ataxia, wide-based gait, dysmetria, and bilateral dysdiadochokinesia. Brain MRI (both T1-weighted and T2-weighted sequences) demonstrated isolated cerebellar vermian and hemispheric atrophy with increased cerebrospinal fluid (CSF) spaces. No endocrine, retinal, or systemic abnormalities were identified. Genetic testing confirmed the same homozygous PNPLA6 variant (c.3547C>T; p.Arg1183Trp). The patients were offered supportive physiotherapy to improve balance and fall precautions, as well as genetic counseling for family planning. This familial case report expands the recognized phenotypic spectrum of PNPLA6-related disorders by demonstrating predominantly cerebellar ataxia without endocrine or retinal involvement. These findings underscore the importance of genetic screening in unexplained adult-onset ataxia, particularly in consanguineous families, even in the absence of classic syndromic features.