INPP5K-related muscular dystrophy caused by a novel synonymous splicing variant in a Chinese patient: a case report

Congenital muscular dystrophies (CMDs) represent a clinically and genetically heterogeneous group of inherited muscle disorders characterized by muscle weakness, hypotonia, dystrophic changes on muscle biopsy, and onset typically in infancy or early childhood. The CMDs encompass a growing number of distinct genetic entities, with over 30 causative genes identified to date, encoding proteins involved in diverse cellular functions including extracellular matrix composition, glycosylation, nuclear envelope structure, and intracellular signaling. Despite significant advances in genetic diagnosis, many patients with suspected CMD remain without a molecular diagnosis, reflecting the extensive genetic heterogeneity of these disorders and the challenges associated with identifying pathogenic variants in non-canonical regions or with atypical mechanisms.

Among the recently identified causes of CMD are variants in the INPP5K gene, which encodes inositol polyphosphate-5-phosphatase K, a phosphoinositide 5-phosphatase that plays a critical role in regulating phosphoinositide signaling, particularly the conversion of phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) to phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)P2). INPP5K-related muscular dystrophy was first described in 2017 by two independent groups, who identified biallelic INPP5K variants in patients with a clinical phenotype characterized by congenital muscular dystrophy, early-onset cataracts, and mild to moderate intellectual disability, with some patients also exhibiting microcephaly and structural brain abnormalities. Since the initial description, additional cases have been reported, but the disorder remains extremely rare, with only approximately 30 patients described in the literature to date, and all reported cases have been from non-Chinese populations.

This case report describes the first Chinese patient with INPP5K-related muscular dystrophy, a 28-year-old male who presented with a notably mild phenotype that significantly expands the clinical spectrum of this disorder. The patient was the second child of non-consanguineous Chinese parents, both of whom were clinically unaffected, and he had a healthy older sister. His perinatal history and early motor developmental milestones were entirely normal, which is somewhat atypical for congenital muscular dystrophy, where hypotonia and motor delay are often present from infancy. The initial disease manifestation was bilateral cataracts requiring surgical correction at age 5, an early-onset cataract that should raise suspicion for an underlying systemic disorder, particularly when accompanied by other systemic manifestations. Neuromuscular symptoms emerged later in adolescence, beginning with postural hand tremors at age 15, followed by progressive lower limb weakness at age 16. Neurological examination at that time revealed muscle weakness (Medical Research Council grade 4/5) in the neck flexors, deltoids, iliopsoas, and gluteal muscles, with a pattern consistent with limb girdle muscular dystrophy. Serum creatine kinase levels were markedly elevated, ranging from 1417 to 4286 U/L (normal range 50-310 U/L), and lactate levels were mildly increased. Electrophysiological studies revealed neurogenic motor unit potentials, although sensory and motor conduction velocities were normal. Interestingly, the patient reported subjective improvement in strength and tremor after self-administering coenzyme Q10, with subsequent examination showing MRC grade 5 power, an anecdotal observation that may suggest a role for mitochondrial dysfunction or oxidative stress in the disease pathophysiology, although this requires further investigation.

Muscle magnetic resonance imaging (MRI) proved to be a particularly valuable diagnostic tool in this case, revealing a characteristic and highly distinctive pattern of selective fatty infiltration and atrophy. Specifically, there was severe involvement of the gluteal muscles and the vasti muscles of the thighs, with striking sparing of the rectus femoris, sartorius, and gracilis muscles. This specific pattern of muscle involvement, with relative sparing of the rectus femoris in particular, has been described in previously reported patients with INPP5K-related muscular dystrophy and appears to be a relatively specific imaging signature for this disorder, providing an important diagnostic clue that can guide genetic testing selection.

The recognition of this characteristic muscle MRI pattern across diverse populations validates its universal diagnostic utility and emphasizes the importance of muscle MRI in the diagnostic evaluation of patients with suspected muscular dystrophy, particularly when genetic testing results are inconclusive or when variants of uncertain significance are identified. Brain MRI in this patient was unremarkable, with no evidence of structural abnormalities, microcephaly, or white matter changes, consistent with the absence of intellectual disability and the overall mild neurological phenotype. Genetic analysis using next-generation sequencing identified compound heterozygous variants in the INPP5K gene: a missense variant c.274C>T, p.(Arg92Cys), and a synonymous variant c.261G>A, p.(Lys87=). While the missense variant was readily recognized as potentially pathogenic, the synonymous variant, which does not alter the encoded amino acid (lysine at position 87), would typically be classified as a benign polymorphism and dismissed in standard bioinformatic analysis pipelines.