Clinical characteristics: Serine deficiency disorders include a spectrum of disease ranging from lethal prenatal-onset Neu-Laxova syndrome to serine deficiency with infantile, juvenile, or adult onset. Neu-Laxova syndrome is characterized by severe intrauterine growth deficiency, microcephaly, congenital bilateral cataracts, characteristic dysmorphic features, limb anomalies, and collodion-like ichthyosis. Infants are typically stillborn or die in early infancy. Infantile-onset serine deficiency is characterized by seizures, microcephaly, developmental delay, intellectual disability, and spastic quadriplegia. Individuals that present with juvenile-onset serine deficiency have seizures and many develop spastic quadriplegia. Adult-onset serine deficiency is characterized by progressive axonal polyneuropathy with ataxia and possible cognitive impairment.
Diagnosis/testing: The diagnosis of a serine deficiency disorder is established in a proband with biallelic pathogenic variants in PHGDH, PSAT1, or PSPH identified by molecular genetic testing.
Management: Treatment – targeted therapy: Early treatment with L-serine supplementation; glycine supplementation with L-serine has been used in some individuals.
Treatment – supportive care: L-serine therapy is more effective than anti-seizure medication for treatment of seizures; developmental and educational support; feeding therapy for persistent feeding issues; treatment of cataracts per ophthalmologist; standard treatments for spasticity and polyneuropathy; preventative dental care for those on oral L-serine powder; social work support and care coordination as needed.
Surveillance: Monitor for seizures, changes in tone, contractures, developmental and educational needs, behavior issues, growth and nutrition, constipation and feeding issues, respiratory issues, musculoskeletal manifestations, and family needs at each visit. Dental evaluation every six months. Assessment of care needs when transitioning from pediatric to adult care.
Agents/circumstances to avoid: Known triggers of seizure activity (e.g., infection, physical stress, emotional stress).
Evaluation of relatives at risk: It is appropriate to evaluate newborn sibs and apparently asymptomatic older and younger sibs of a proband to identify as early as possible those who would benefit from prompt initiation of L-serine treatment.
Genetic counseling: Serine deficiency disorders are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a serine deficiency-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the serine deficiency-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.
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