**Background:** Hypomyelinating leukodystrophies are a genetically heterogeneous group of white matter disorders characterized by impaired myelin deposition in the central nervous system. Over the past decade, mutations in genes beyond those encoding structural oligodendrocyte proteins—including transcription factors, tRNA synthetases, and RNA polymerase subunits—have been implicated. TMEM106B, encoding a lysosomal transmembrane protein involved in late endosome and lysosome trafficking, has recently been linked to hypomyelinating leukodystrophy (HLD16; MIM 617964), neurodegenerative disorders, and brain aging. To date, only a handful of cases have been reported, all in European or Chinese populations.
**Methods:** The patient, a 5-year-old Saudi male of Arab descent, presented at age 3 with horizontal nystagmus, hypotonia, elevated leg muscle tone, and increased tendon reflexes. Developmental history revealed delayed motor milestones (sitting at 1.5 years, walking at 2.10 years). At age 5, he could run and climb stairs independently. Fine motor skills and receptive language were age-appropriate, but expressive language showed poor pronunciation and grammar; he could construct 4–6 word sentences. IQ was not tested. Hearing was normal, and there was no seizure history. Neurological examination at age 5 revealed dysarthria, gait ataxia, dysmetria, brisk deep tendon reflexes with low plantar reflexes, and rapid bilateral nystagmus. No dysmorphic features or internal organ involvement were noted. Both parents (father aged 42, mother aged 34) were healthy and unrelated. Metabolic and biochemical markers, including lactic acid and quantitative amino acids, were normal. Brain MRI at age 4 showed clear hypomyelination with T1/T2 signal discrepancy and increased white matter signal on T2 and FLAIR images in supra- and infratentorial regions, including the external and internal capsules and corticospinal tract in the brainstem, indicating extensive demyelination. Whole-exome sequencing was performed using Twist Human Core Exome Plus kit on an Illumina platform with ≥20x coverage for >98% of targeted bases. Variants with MAF <1% in gnomAD and disease-causing variants in HGMD, ClinVar, or CentoMD were evaluated.
**Key Results:** Sequencing identified a heterozygous de novo missense variant in TMEM106B: c.754G>A (p.Asp252Asn), causing an aspartate-to-asparagine substitution at position 252. This variant was classified as pathogenic (class 1) per CENTOGENE and ACMG guidelines. It had been previously reported by Simons et al. (PMID: 29186371) in four unrelated patients with brain hypomyelination (de novo in three; mosaic in the mildly affected father of the fourth) and by Yan et al. (PMID: 29444210) as de novo in one patient. Comparison with five previously reported cases (four European, one Chinese; ages 3–38 years) showed consistent phenotypic features: all had gross motor delay and speech delay; nystagmus was present in all (horizontal, vertical, pendular, or rotatory); gait ataxia was present in four of five; intellectual disability ranged from mild to severe; seizures occurred in two patients; and brain MRI showed hypomyelination in all, with one patient having a thin corpus callosum. The current patient's phenotype was relatively mild: he had mild intellectual disability, no seizures, and could walk independently.
**Clinical Implications:** This is the first reported case of TMEM106B-related hypomyelinating leukodystrophy in the Middle East and Saudi Arabia, expanding the ethnic diversity of known cases. The consistent phenotype across populations—early-onset nystagmus, hypotonia, motor delay, ataxic gait, and diffuse hypomyelination on MRI—supports a specific genotype-phenotype correlation for the Asp252Asn variant. The relatively mild clinical course in this patient, compared to the most severely affected patient who was nonverbal at age 19, suggests variable expressivity even with the same mutation. TMEM106B is abundantly expressed in neurons and oligodendrocytes and localized to late endosome/lysosome compartments; the Asp252Asn mutation in the cytoplasmic domain affects highly conserved residues. Functional studies in oligodendroglial cell lines have shown that the mutant protein significantly reduces mRNA production of key myelin genes, decreases branching, and increases cell mortality. The findings also suggest a novel role for zinc homeostasis in oligodendrocyte development and myelin production, as TMEM163 variations have been linked to hypomyelination leukodystrophy. This case reinforces the importance of including TMEM106B in diagnostic gene panels for hypomyelinating leukodystrophies, particularly in populations where it has not been previously reported.