Methionine synthase deficiency: Variable clinical presentation and benefit of early diagnosis and treatment.

Methionine synthase deficiency (cblG complementation group) is a rare inborn error of metabolism affecting the homocysteine re-methylation pathway. It leads to a biochemical phenotype of hyperhomocysteinemia and hypomethioninemia. The clinical presentation of cblG is variable, ranging from seizures, encephalopathy, macrocytic anemia, hypotonia, and feeding difficulties in the neonatal period to onset of psychiatric symptoms or acute neurologic changes in adolescence or adulthood. Given the variable and nonspecific symptoms seen in cblG, the diagnosis of affected patients is often delayed. Medical management of cblG includes the use of hydroxocobalamin, betaine, folinic acid, and in some cases methionine supplementation. Treatment has been shown to lead to improvement in the biochemical profile of affected patients, with lowering of total homocysteine levels and increasing methionine levels. However, the published literature contains differing conclusions on whether treatment is effective in changing the natural history of the disease. Herein, we present five patients with cblG who have shown substantial clinical benefit from treatment with objective improvement in their neurologic outcomes. We demonstrate more favorable outcomes in our patients who were treated early in life, especially those who were treated before neurologic symptoms manifested. Given improved outcomes from treatment of presymptomatic patients, cblG warrants inclusion in newborn screening.

Neonatal Onset Interstitial Lung Disease as a Primary Presenting Manifestation of Mucopolysaccharidosis Type I.

We describe two cases of neonatal onset interstitial lung disease eventually diagnosed as mucopolysaccharidosis type I (MPS I). In both cases, evaluation led to lung biopsy, pathology review, and identification of glycogen deposition. Pulmonary interstitial glycogenosis (PIG) was considered as a clinical diagnosis in case one; however, further review of electron microscopy (EM) was more consistent with MPS I rather than PIG. Both cases were confirmed to have MPS I by enzyme and molecular analysis. Neonatal interstitial lung disease is an atypical presentation for MPS I which is likely under-recognized. Diagnosis through clinical guidelines and a multidisciplinary approach had a major impact on patient management. The diagnosis of MPS I prompted timely initiation of enzyme replacement therapy (ERT) and the patients ultimately underwent hematopoietic stem cell transplantation (HSCT) to improve symptomatic outcomes. In addition to treatment, immediate precautionary recommendations were made to avoid potentially catastrophic outcomes associated with cervical instability. These cases add to the clinical spectrum of MPS I in the newborn period. They further illustrate the difficulties in early recognition of the disease, and importance of a definitive diagnosis of MPS I in infants with interstitial lung disease.

Somatic mosaicism for a novel PDHA1 mutation in a male with severe pyruvate dehydrogenase complex deficiency.

Pyruvate dehydrogenase complex (PDC) deficiencies are mostly due to mutations in the X-linked PDHA1 gene. Males with hemizygous PDHA1 mutations are clinically more severely affected, while those with mosaic PDHA1 mutations may manifest milder phenotypes. We report a patient harboring a novel, mosaic missense PDHA1 mutation, c.523G > A (p.A175T), with a severe clinical presentation of congenital microcephaly, significant brain abnormalities, persistent seizures, profound developmental delay, and failure to thrive. We review published cases of PDHA1 mosaicism.