EMC1 – Cerebellar Atrophy, Visual Impairment, and Psychomotor Retardation

EMC1 encodes a subunit of the endoplasmic reticulum membrane protein complex critical for membrane protein insertion and homeostasis. Biallelic EMC1 variants cause an autosomal recessive neurodevelopmental syndrome characterized by cerebellar atrophy, visual impairment, and psychomotor retardation (CAVIPMR). The clinical validity of this association is supported by multiple unrelated families with consistent segregation and functional concordance, supporting a Strong classification.

Five consanguineous Kuwaiti families were found to harbor a homozygous missense variant, c.245C>T (p.Thr82Met), in eight affected individuals presenting with early-onset visual abnormalities, hypotonia, and global developmental delay (PMID:38784058). Segregation analysis confirmed homozygosity in all affected and carrier status in parents. Previous reports described biallelic loss-of-function and missense EMC1 variants in three additional families with similar neurodevelopmental phenotypes (PMID:26942288).

The variant spectrum includes the recurrent founder missense change c.245C>T (p.Thr82Met) and multiple loss-of-function alleles such as frameshift and nonsense mutations. Essential splice-site variants and deep intronic changes have been shown to cause aberrant splicing and premature termination, as confirmed by RNA sequencing assays (PMID:29271071). In total, at least 14 probands across 10 autosomal recessive families have been documented.

Clinical features are consistent and include global developmental delay, microcephaly (HP:0000252), axial hypotonia (HP:0008936), hyperreflexia (HP:0001347), visual impairment (HP:0000505), cerebellar atrophy (HP:0001272), seizure (HP:0001250), chorea (HP:0002072), and failure to thrive (HP:0001508). Notably, chorea was newly recognized in the Kuwaiti cohort, expanding the phenotypic spectrum.

Functional studies demonstrate that EMC1 deficiency disrupts multipass membrane protein topogenesis. Xenopus emc1 knockdown impaired neural crest cell development via reduced WNT signaling, rescuable by β-catenin supplementation (PMID:31904590), while Drosophila models of EMC1 dosage imbalance resulted in glial-specific lethality, confirming loss-of-function alleles (PMID:35234901).

No conflicting evidence has been reported. Integration of genetic and experimental data establishes EMC1 loss-of-function and haploinsufficiency as the mechanism in AR CAVIPMR. Screening for EMC1 variants, particularly c.245C>T (p.Thr82Met), should be incorporated into diagnostic panels for infants presenting with early visual impairment, hypotonia, and developmental delay.

Key Take-home: EMC1 biallelic variants cause a consistent autosomal recessive neurodevelopmental syndrome with cerebellar atrophy and visual impairment, supporting targeted genetic testing for early diagnosis.

References

• Neurology: Genetics • 2024 • Tribal Founder EMC1 Variant in 5 Kuwaiti Families Expands Phenotypic Spectrum of EMC1-Related Disorder. PMID:38784058
• American Journal of Human Genetics • 2016 • Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy. PMID:26942288
• Molecular Genetics & Genomic Medicine • 2018 • A novel splice variant in EMC1 is associated with cerebellar atrophy, visual impairment, psychomotor retardation with epilepsy. PMID:29271071
• The Journal of Clinical Investigation • 2020 • Disrupted ER membrane protein complex-mediated topogenesis drives congenital neural crest defects. PMID:31904590
• Human Molecular Genetics • 2022 • De novo variants in EMC1 lead to neurodevelopmental delay and cerebellar degeneration and affect glial function in Drosophila. PMID:35234901

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