Ichthyosis, Spastic Quadriplegia, And Mental Retardation

A number sign (#) is used with this entry because of evidence that ichthyosis, spastic quadriplegia, and mental retardation (ISQMR) is caused by homozygous mutation in the ELOVL4 gene (605512) on chromosome 6q14.

Description

ISQMR is a severe autosomal recessive disorder characterized by ichthyosis apparent from birth, profound psychomotor retardation with essentially no development, spastic quadriplegia, and seizures (summary by Aldahmesh et al., 2011).

Clinical Features

Aldahmesh et al. (2011) reported 2 unrelated patients, both born of 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 noted to have a collodion membrane covering the skin at birth, which resolved and was replaced with dry ichthyotic skin affecting all regions of the body. He showed profound developmental delay and was severely handicapped with little interest in his surroundings when examined at age 6 years. At age 4 months, he developed frequent refractory seizures. He also had severe hypertonia in the upper and lower extremities and was generally immobile, consistent with spastic quadriplegia. Although ophthalmologic examination was limited, he had a normal electroretinogram, normal macula, and high myopia. Brain MRI showed severely delayed myelination and brain atrophy. Other features included recurrent bronchial asthmatic attacks, bilateral inguinal hernias, small testicular size, and loss of most of his teeth. There were no clear dysmorphic features. The mother's eye examination was completely normal, whereas the father's eye examination showed some drusen-like flecks in the macula, which may have been due to heavy smoking. The second patient showed dry skin shortly after birth, but no collodion membrane. The skin later had generalized erythematous ichthyosis with fine scales over most of the body but not on the face. The hair and nails appeared normal. He had profound psychomotor delay and developed myoclonic seizures at 2 months. He had very poor growth and microcephaly, but no dysmorphic features. Other features included hypotonia in all 4 limbs, scissoring and contractures of the lower extremities, and unilateral inguinal hernia. Ophthalmologic exam showed no cataract or macular abnormalities, but there was temporal pallor in both eyes and photophobia, and visual evoked potentials were abnormal. The patient was bedridden and never gained the ability to sit, speak, or feed himself. He died from aspiration at age 2 years; a similarly affected sib died at 6 months of age. The combination of ichthyosis, intellectual disability, and spastic quadriplegia in these patients was reminiscent of Sjogren-Larsson syndrome (SLS; 270200).

Inheritance

The transmission pattern of ISQMR in the families reported by Aldahmesh et al. (2011) was consistent with autosomal recessive inheritance.

Molecular Genetics

By autozygosity mapping followed by exome sequencing in a Saudi Arabian boy with ichthyosis, spastic quadriplegia, and mental retardation, Aldahmesh et al. (2011) identified a homozygous mutation in the ELOVL4 gene (605512.0005). Analysis of 15 additional patients with similar features identified 1 patient with a different ELOVL4 mutation (605512.0006). The findings highlighted an important role for very long chain fatty acids (VLCFAs) in early brain development and in the integrity of the epidermal water barrier. Aldahmesh et al. (2011) noted the phenotypic overlap with the mouse model of homozygous Elovl4 null mutations (see ANIMAL MODEL).

Animal Model

Vasireddy et al. (2007) observed that mice homozygous for a null Elovl4 allele had scaly, wrinkled skin with severely compromised epidermal permeability barrier function and died within a few hours after birth. Histopathologic evaluation of the homozygous pups revealed no apparent abnormality of vital internal organs; however, skin histology showed an abnormally compacted stratum corneum (SC), and electron microscopy revealed deficient epidermal lamellar body contents and lack of normal SC lamellar membranes. Lipid analyses of epidermis from homozygous mice revealed a global decrease in very long chain fatty acids (VLCFAs) in both the ceramide/glucosylceramide and free fatty-acid fractions. In addition, Elovl4 del/del skin was devoid of the epidermal-unique omega-O-acylceramides, which are key hydrophobic components of the extracellular lamellar membranes in mammalian SC. Vasireddy et al. (2007) concluded that ELOVL4 is required for generating VLCFAs critical to epidermal barrier function, and that lack of epidermal omega-O-acylceramides is incompatible with survival in a dessicating environment.