Salt And Pepper Developmental Regression Syndrome

A number sign (#) is used with this entry because of evidence that salt and pepper developmental regression syndrome (SPDRS) is caused by homozygous or compound heterozygous mutation in the ST3GAL5 gene (604402), which encodes sialyltransferase-9 (SIAT9), also known as GM3 synthase, on chromosome 2p11.

Description

Salt and pepper developmental regression syndrome, also known as Amish infantile epilepsy syndrome, is an autosomal recessive neurocutaneous disorder characterized by infantile onset of refractory and recurrent seizures associated with profoundly delayed psychomotor development and/or developmental regression as well as abnormal movements and visual loss (summary by Fragaki et al., 2013). Affected individuals develop hypo- or hyperpigmented skin macules on the trunk, face, and extremities in early childhood (summary by Boccuto et al., 2014). Not all patients have overt seizures (Lee et al., 2016).

Clinical Features

Simpson et al. (2004) described an autosomal recessive infantile-onset epilepsy syndrome associated with developmental stagnation and blindness in the Old Order Amish of Geauga County, Ohio. All surviving members of the 2 branches of the single large family could be traced back to a fifth-generation common ancestor. All affected children were born at full term. The first symptoms were noted between the ages of 2 weeks and 3 months, and consisted primarily of irritability with additional poor feeding, vomiting, and failure to thrive. Gastrostomy feeding tubes were required in 2 of the 4 affected children in family A and in all affected children in family B. Seizure activity started during the first year of life, with all affected children suffering from generalized tonic-clonic (grand mal) seizures, as well as other seizure types. In at least one case, startle myoclonus was observed before generalized tonic-clonic seizures. Seizure control was difficult, requiring multiple medications and, for 2 children in 1 family, vagus nerve stimulators. Although the generalized seizures were eventually largely controlled, other seizure types, including brief tonic spasms, episodes of eye deviation, or startle from sleep, were not fully suppressed. The onset of seizure activity was accompanied by profound developmental stagnation, with evidence of regression. Affected children were unable to sit unsupported, reach, or walk, and were nonverbal. Nonpurposeful arm movements had a choreoathetoid component. Eye contact and visual function deteriorated, probably owing to cortical impairment, although there was some evidence of optic atrophy. Electroencephalograms ultimately showed multifocal epileptiform discharges superimposed on diffuse slow background activity. Brain MRI initially showed no structural abnormalities, but studies at older ages showed diffuse atrophy.

The 2 sibships with this disorder reported by Simpson et al. (2004), related as double fifth cousins, contained a total of 9 affected individuals. Only 1 had died (aged 27 months). Four of the other individuals had survived into their teens, the oldest being aged 18, thanks to excellent home care which included gastric tube feeding (Cross, 2004).

The same disorder may have been described by Max et al. (1974). They studied an infant who had poor physical and motor development, coarse facies, macroglossia, gingival hypertrophy, squat hands and feet, flexor contractures of the fingers, thickened, loose, hirsute skin, bilateral large inguinal hernias, an enlarged liver and spleen, and normal fundi. Shortly after birth the patient became limp and unresponsive, dying at 3 and a half months of age. The accumulation of ganglioside GM3 (hematoside) was established by quantitative lipid analysis of fresh-frozen postmortem samples of brain and liver. Higher ganglioside homologs were completely absent. This unusual ganglioside pattern suggested that the defect in GM3 sphingolipodystrophy was in ganglioside biosynthesis, in contrast to previously described sphingolipidoses, which are due to deficiencies of catabolic enzymes.

Saul et al. (1983) reported 3 African American sibs with delayed psychomotor development from infancy, resulting in severe mental retardation associated with pigmentary skin changes that developed after age 2 years. The patients also had dysmorphic facial features, including midface hypoplasia and prognathism. Other features included microcephaly, choreoathetosis, hypertonicity, scoliosis, and nonspecific EKG changes. One patient had seizures. The pigmentary changes were described as 'salt and pepper' macules ranging from 1 to 5 mm in diameter on the trunk, extremities, and face. Histologic examination of a hyperpigmented lesion showed increased pigmentation consistent with a freckle. The patients were nonverbal and nonambulatory in their early teenage years.

Farukhi et al. (2006) reported detailed ophthalmologic studies of 4 Amish patients from 2 related sibships with GM3 synthase deficiency. The children were 13 months, 6 years, 6 years, and 13 years of age. All had normal slit-lamp examinations and preserved retinal function. However, all had pale optic nerves with atrophy. These findings suggested that visual loss in this disorder results from cortical visual impairment and optic nerve defects rather than retinal involvement.

Fragaki et al. (2013) reported 2 sibs, born of consanguineous French parents, with infantile onset of severe refractory epilepsy with myoclonus and status epilepticus. Both had delayed psychomotor development and failure to thrive. Choreoathetoid movements appeared at around 15 months of age, and both showed further neurologic deterioration at 2 to 3 years of age. One developed hypotonic tetraparesis with visual impairment, and the other was deaf and blind with pallor of the optic nerve. Serum lactate was increased. Brain MRI showed white matter lesions and cortical atrophy, including in the occipital cortex, which indicated cortical blindness rather than retinal disease. Fibroblasts from 1 of the sibs showed decreased oxygen consumption, and liver biopsy showed decreased activity of quinone-dependent complexes I+III and II+III, consistent with a respiratory chain defect. Treatment with CoQ10 supplements resulted in transient subjective improvement in eye contact and interactivity, but the results were not sustained.

In a study of 38 Amish patients with GM3 synthase deficiency ranging in age from 0.5 to 25 years, Wang et al. (2013) found that 20 patients had hyperpigmented macules that increased in number with age. The macules resembled large freckles or small lentigines, were between 2 and 5 mm in diameter, and were usually found bilaterally on the extremities, especially the dorsal aspects of the hands and feet. Occasional sites included the hips, face, chest wall, and back. No pigmentary lesions were seen on mucosal surfaces or nailbeds. Lesions were found in 86% of patients aged 6 years or older and in 93% of patients aged 11 years or older, but no lesions were found in children younger than 3 years of age. Seven of the 20 patients also had areas of depigmentation that had well-defined borders and showed variation in size and shape. In at least 3 cases, the parents reported that the hyperpigmentation, after being present for years, almost disappeared. The findings suggested that these cutaneous pigmentary changes may serve as useful clues to aid in the diagnosis of this metabolic disorder.

Lee et al. (2016) reported 2 Korean sisters, born of unrelated parents, with severe mental retardation associated with GM3 synthase deficiency. The proband presented with developmental regression at age 6 months after normal early development for the first 4 months of life. She was irritable and had jerky movements and nystagmus without seizures. Brain imaging was normal. At age 4 years, she could not sit, roll over, make eye contact, or speak. Her older sister, who was less severely affected, presented at age 2 years with global developmental delay and inability to walk. She had microcephaly, irritability, and choreoathetotic movements. She could eventually walk a few steps without assistance, but did not speak. Both patients developed hand stereotypies with a lack of purposeful hand movements suggestive of Rett syndrome (RTT; 312750), but sequencing of Rett-associated genes showed no abnormalities. Both patients also had increased serum lactate. Neither patient had abnormalities of the optic nerve or clinical seizures; only the older patient showed pepper-like skin pigmentation on the hands and feet at age 6 years.

Inheritance

The transmission pattern of GM3 synthase deficiency in the family reported by Fragaki et al. (2013) was consistent with autosomal recessive inheritance.

Mapping

By homozygosity mapping in an Amish family segregating an infantile-onset epilepsy syndrome, Simpson et al. (2004) demonstrated linkage to a 5.1-cM region on 2p12-p11.2, with a maximum multipoint lod score of 6.84 around marker D2S2162. None of the unaffected sibs or parents were homozygous across this interval.

Molecular Genetics

By sequencing several genes in the region of linkage on 2p12-p11.2 identified in an Amish family segregating an infantile-onset epilepsy syndrome, Simpson et al. (2004) identified a nonsense mutation in the SIAT9 gene (604402.0001), whose product functions as a GM3 synthase. The affected children completely lacked GM3 and its downstream biosynthetic derivatives but had increased levels of the immediate precursor to GM3, lactosylceramide.

In 2 sibs, born of consanguineous French parents, with refractory epilepsy and delayed psychomotor development, Fragaki et al. (2013) identified a homozygous R288X mutation in the SIAT9 gene, which was the same mutation identified by Simpson et al. (2004) in Amish patients with a similar disorder. The mutation, which was identified by exome sequencing, segregated with the disorder in the family. Mass spectrometry analysis of patient fibroblasts showed complete absence of GM3 ganglioside and its biosynthetic derivatives and an upregulation of the alternative globoside pathway. Fibroblasts also showed a decrease in mitochondrial membrane potential, consistent with secondary dysfunction of the respiratory chain, as well as increased apoptosis.

In 2 sibs originally reported by Saul et al. (1983) as having 'salt and pepper' mental retardation syndrome, Boccuto et al. (2014) identified a homozygous missense mutation in the ST3GAL5 gene (E332K; 604402.0002). The mutation was found by whole-exome sequencing. Patient fibroblasts showed no GM2 or GM3, consistent with a loss of ST3GAL5 function. Analysis of the glycolipid profile in patient cells and plasma showed a shift toward ceramides with longer fatty acid chain length. Microarray analysis of glycosyltransferase mRNAs detected modestly increased expression of ST3GAL5 and greater changes in transcripts encoding enzymes that lie downstream of ST3GAL5 and in other glycosphingolipid biosynthetic pathways. Comprehensive glycomic analysis of N-linked, O-linked, and glycosphingolipid glycans revealed collateral modulation of glycoprotein sialylation in response to the loss of complex gangliosides. Morpholino knockdown of st3gal5 in zebrafish embryos caused increased neuronal cell death that could be rescued by expression of the wildtype gene. The findings indicated that human neural cells are extremely sensitive to ST3GAL5 deficiency and altered glycosphingolipid synthesis.

In 2 Korean sisters with salt and pepper developmental regression syndrome, Lee et al. (2016) identified compound heterozygous missense mutations in the ST3GAL5 gene (C195S; 604402.0003 and G201R; 604402.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Plasma gangliosides in the 2 sibs were barely detectable, suggesting a loss of function.

Nomenclature

Purists insist that this should be called a symptomatic epilepsy syndrome since epilepsy is only a manifestation of the underlying defect in GM3 synthesis (Crosby, 2004).