A case of Joubert Syndrome and NPC1 mutation in a 7-year-old girl: presented with neuromotor developmental delay and ataxia.

Abstract

Joubert Syndrome (JS) is a rare neurodevelopmental disorder characterized by cerebellar ataxia, oculomotor apraxia, and the characteristic "molar tooth sign" on brain MRI. Niemann - Pick Disease Type C (NPC) is an autosomal recessive lysosomal storage disorder associated with progressive neurological involvement, including ataxia and vertical supranuclear gaze palsy. Although these disorders have distinct genetic and pathophysiological mechanisms, they share overlapping clinical features such as ataxia, oculomotor abnormalities, and developmental delay, which may complicate the diagnostic process. We evaluated a 7-year-old Afghan girl with speech impairment and neuromotor developmental delay. Neurological and radiological assessments were conducted, followed by genetic analysis using next-generation sequencing to explore underlying mutations. Neurological examination revealed cerebellar ataxia, oculomotor apraxia, and dysmetria, consistent with JS. Brain MRI demonstrated the characteristic molar tooth sign. Genetic testing identified homozygous mutations in the NPC1 gene (c.1123A > G, p.Thr375Ala) and the AHI1 gene (c.2671C > T, p.R891). Despite the NPC1 mutation, no classical signs of NPC - such as vertical gaze palsy or clinical deterioration - were observed. Family history revealed a bedridden cousin, though no diagnostic information was available. Based on genetic findings, miglustat therapy was initiated. This case illustrates the diagnostic challenges arising from coexisting pathogenic mutations in genes associated with different neurological syndromes. Although clinical features primarily aligned with Joubert Syndrome, the possibility of subclinical or emerging Niemann-Pick Disease Type C could not be excluded. Genetic overlap emphasizes the importance of integrated clinical and molecular evaluation in rare neurogenetic disorders.