SMPD4 – Neurodevelopmental Disorder with Microcephaly, Arthrogryposis, and Structural Brain Anomalies

SMPD4 encodes sphingomyelin phosphodiesterase 4, a magnesium-dependent neutral sphingomyelinase that hydrolyzes sphingomyelin into ceramide and phosphorylcholine within the endoplasmic reticulum and nuclear envelope. Loss-of-function variants in SMPD4 have been associated with a rare syndromic neurodevelopmental disorder characterized by microcephaly, arthrogryposis, and structural brain anomalies, officially designated as MONDO:0032838. This syndrome, commonly referred to as NEDMABA, presents with severe prenatal and postnatal neurological impairment. Inheritance follows an autosomal recessive pattern with biallelic null alleles required for disease manifestation. Affected individuals often have intrauterine growth retardation and early-onset developmental delays. The clinical presentation includes both central and peripheral neurological involvement, underscoring the critical role of SMPD4 in neurodevelopment.

To date, four unrelated probands have been reported with biallelic null variants in SMPD4, each presenting with a consistent NEDMABA phenotype (PMID:35651939; PMID:38690959; PMID:37882972). The original case report described a Chinese female with prenatal intrauterine growth restriction, microcephaly, arthrogryposis, hypertonicity, seizures, and hypomyelination on MRI carrying c.1347C>G (p.Tyr449Ter) in homozygosity alongside a whole-gene deletion (PMID:35651939). A prenatal study identified a fetus with microcephaly and arthrogryposis harboring compound heterozygous variants including c.387-1G>A and a ~59-kb deletion (PMID:38690959). Further exome sequencing revealed two unrelated patients: one homozygous for c.740_741del (p.Val247GlufsTer21), and another compound heterozygous for c.2124_2125del (p.Phe709Ter) and c.1188+2dup, establishing recurrence across populations (PMID:37882972). Absence of identified hypomorphic or regulatory variants suggests a primary loss-of-function mechanism.

Biallelic variants include nonsense, frameshift, and canonical splice-site alterations, as well as multi-exon deletions, collectively ablating SMPD4 function. Specific alleles include c.1347C>G (p.Tyr449Ter), c.740_741del (p.Val247GlufsTer21), c.2124_2125del (p.Phe709Ter), and c.1188+2dup causing exon 13 skipping. Structural variants range from whole-gene deletion to partial intragenic deletions. No recurrent founder alleles have emerged, indicating genetic heterogeneity. Reported variant frequencies in gnomAD are extremely low, with no homozygous LoF alleles in population databases. These data align with a recessive LoF model without dominant-negative effects.

Functional assays using minigene constructs and patient-derived RNA have demonstrated that canonical splice-site and frameshift variants induce exon skipping and premature termination codons, leading to nonsense-mediated mRNA decay (PMID:37882972). Reduced SMPD4 transcript levels correlate with loss of sphingomyelinase activity in cellular studies, although quantitative enzyme assays have yet to be published. Localization studies confirm that wild-type SMPD4 resides in the endoplasmic reticulum and nuclear envelope, whereas mutant proteins are undetectable by immunoblot. No animal models are currently described. The experimental data support haploinsufficiency as the primary disease mechanism. Concordance between in vitro findings and patient phenotypes strengthens the functional link.

Clinically, NEDMABA presents with congenital microcephaly (HP:0000252) and arthrogryposis multiplex congenita (HP:0002804) often evident on prenatal ultrasound. Additional features in reported cases include intrauterine growth retardation (HP:0001511), hypertonia (HP:0001276), early-onset seizures (HP:0001250), and CNS hypomyelination (HP:0003429), reflecting widespread neurodevelopmental disruption. Patients commonly exhibit profound global developmental delay and may develop secondary complications such as insulin-dependent diabetes mellitus and sensorineural hearing loss. Brain MRI typically reveals simplified gyral patterns, cerebellar hypoplasia, and thin corpus callosum. The severity of neurological impairment underscores the importance of early genetic diagnosis. Carrier parents are phenotypically unaffected.

In summary, SMPD4 fulfills ClinGen criteria for a moderate gene-disease association with autosomal recessive inheritance, supported by multiple unrelated cases and concordant functional data. The current body of evidence includes four probands with biallelic LoF variants and demonstration of transcript degradation, meeting the threshold for moderate clinical validity. Additional cases are needed to reach strong or definitive classification, particularly segregation in extended families and in vivo models. Nevertheless, SMPD4 molecular testing should be integrated into diagnostic panels for congenital microcephaly and arthrogryposis. Identification of pathogenic SMPD4 variants enables accurate diagnosis, informed genetic counseling, and appropriate prenatal decision-making. Key Take-home: Biallelic loss-of-function variants in SMPD4 cause autosomal recessive NEDMABA, supporting its inclusion in early neurodevelopmental disorder testing.

References

• Frontiers in Genetics • 2022 • Case Report: Novel Biallelic Null Variants of SMPD4 Confirm Its Involvement in Neurodevelopmental Disorder With Microcephaly, Arthrogryposis, and Structural Brain Anomalies PMID:35651939
• Psychiatric Genetics • 2024 • Whole-exome-based single nucleotide variants and copy number analysis for prenatal diagnosis of compound heterozygosity of SMPD4. PMID:38690959
• Neurogenetics • 2024 • Two novel cases of biallelic SMPD4 variants with brain structural abnormalities. PMID:37882972

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