Rationale: Multiple system atrophy (MSA) is primarily a sporadic neurodegenerative disorder, and a positive family history is considered against the diagnosis. While rare familial clusters are reported, they pose a significant diagnostic challenge. This report describes 2 cousins with phenotypically classic MSA who underwent genetic testing to investigate a potential shared etiology, leading to a diagnosis of a rare MSA mimic. Patient concerns: Case 1: a 77-year-old male presented with Parkinsonism (bradykinesia, resting tremor) and neurogenic orthostatic hypotension. Case 2: a 55-year-old female, case 1’s 1st cousin, presented with progressive limb ataxia, dysarthria, and neurogenic orthostatic hypotension. Both patients reported a poor therapeutic response to levodopa and a progressive decline in functional mobility. Diagnoses: Initially, case 1 was diagnosed with clinically probable MSA with predominant Parkinsonism, and case 2 was diagnosed with clinically probable MSA with predominant cerebellar ataxia (MSA-C). However, post-genetic analysis, case 1 was definitively diagnosed with late-onset metachromatic leukodystrophy (MLD). Case 2 remained clinically classified as MSA-C as no significant genetic variants were identified. Interventions: Clinical evaluation and levodopa trials were conducted for both patients. To investigate the suspected familial MSA cluster, whole-genome sequencing was performed for both individuals to identify shared pathogenic variants. Outcomes: Whole-genome sequencing identified biallelic pathogenic mutations in the arylsulfatase A gene in case 1, confirming MLD. No shared genetic etiology was found in case 2. The discovery of MLD in case 1 provided an alternative metabolic explanation for his symptoms, thereby refuting the initial hypothesis of a shared familial MSA link between the 2 cousins. Lessons: This case highlights that late-onset MLD can closely mimic the clinical phenotype of MSA. Clinicians should maintain a high index of suspicion when encountering familial MSA. A comprehensive genetic evaluation is essential in such cases to exclude metabolic or hereditary mimics before concluding a rare familial presentation of a typically sporadic synucleinopathy.
Jeong et al. (Fri,) studied this question.