Ichthyosis, spastic quadriplegia, and mental retardationQ87.13

Ichthyosis-spastic tetraplegia-mental retardation syndrome, or ISQMR, is a severe autosomal recessive systemic disorder with congenital ichthyosis, profound psychomotor retardation, growth failure, spastic tetraplegia, and seizures (Aldahmesh MA et al. 2011).

Evidence suggests a homozygous mutation in the ELOVL4 gene (605512.0005; Aldahmesh et al. 2011). Analysis of 15 additional patients with similar characteristics identified one patient with a different ELOVL4 mutation (605512.0006).

Aldahmesh et al (2011) reported two unrelated patients, both born to consanguineous parents, with a severe neurodevelopmental disorder associated with ichthyosis. The patients were of Saudi Arabian and Asian Indian descent, respectively. The first patient was born as a "collodion baby ". He showed profound developmental delay and, on examination, was severely retarded at 6 years of age and showed little interest in his environment. At 4 months of age, he developed frequent refractory seizures. He also had severe hypertonia in the upper and lower extremities and was generally immobile, consistent with spastic quadriplegia.

MRI of the brain showed severely delayed myelination and brain atrophy. Furthermore, recurrent asthma attacks and bilateral inguinal hernias presented. Deficient Dentition.

The second patient presented with dry, scaly skin shortly after birth. Later, generalized erythematous ichthyosis with fine scales presented over most of the body but not the face. The hair and nails appeared normal. He had marked psychomotor delay and developed myoclonic seizures at 2 months of age. Furthermore, growth retardation and microcephaly. The patient was bedridden and never gained the ability to sit, speak, or feed himself. He died of aspiration at 2 years of age; a similarly affected sibling died at 6 months of age. The combination of ichthyosis, mental retardation, and spastic quadriplegia in these patients was reminiscent of Sjögren-Larsson syndrome (OMIM: 270200).

Diociaiuti A et al (2021) reported 2 Italian children with a homozygous ELOVL4 frameshift mutation. Both infants were born with a collodion membrane followed by diffuse mild hyperkeratosis and scaling, localized erythema, and palmoplantar keratoderma. One infant exhibited mild facial dysmorphism. They suffered from failure to thrive and severe gastroesophageal reflux with pulmonary aspiration. The patients had axial hypotonia, limb hypertonia, and lack of head control with poor eye contact from infancy.

Ultrastructural examination of the skin revealed abnormalities of the lamellar bodies with altered release in the intracellular spaces of the epidermal granular and stratum corneum layers (Diociaiuti A et al. 2021).

In animal experiments, Vasireddy et al. (2007) demonstrated that mice homozygous for an Elovl4 null allele had scaly, wrinkled skin with severely impaired epidermal permeability barrier function and died within hours of birth. However, they skin histology showed abnormally compacted stratum corneum (SC), electron microscopy revealed deficient epidermal lamellar body content and absence of normal SC lamellar membranes.

1. Aldahmesh MA et al (2011) Recessive mutations in ELOVL4 cause ichthyosis, intellectual disability, and spastic quadriplegia. Am J Hum Genet 89: 745-750.
2. Diociaiuti A et al (2021) Two Italian Patients with ELOVL4-Related Neuro-Ichthyosis: Expanding the Genotypic and Phenotypic Spectrum and Ultrastructural Characterization. Genes (Basel) 12:343.
3. Vasireddy V et al. (2007) Loss of functional ELOVL4 depletes very long-chain fatty acids (greater than C28) and the unique omega-O-acylceramides in skin leading to neonatal death. Hum Molec Genet 16: 471-482.