Phosphomannomutase 2 (PMM2‐CDG) is the most common congenital disorder of N‐glycosylation and is caused by a deficient PMM2 activity. The clinical presentation and the onset of PMM2‐CDG vary among affected individuals ranging from a severe antenatal presentation with multisystem involvement to mild adulthood presentation limited to minor neurological involvement. Management of affected patients requires a multidisciplinary approach. In this article, a systematic review of the literature on PMM2‐CDG was conducted by a group of international experts in different aspects of CDG. Our managment guidelines were initiated based on the available evidence‐based data and experts' opinions. This guideline mainly addresses the clinical evaluation of each system/organ involved in PMM2‐CDG, and the recommended management approach. It is the first systematic review of current practices in PMM2‐CDG and the first guidelines aiming at establishing a practical approach to the recognition, diagnosis and management of PMM2‐CDG patients.

Thiamine transporter-2 deficiency is caused by mutations in the SLC19A3 gene. As opposed to other causes of Leigh syndrome, early administration of thiamine and biotin has a dramatic and immediate clinical effect. New biochemical markers are needed to aid in early diagnosis and timely therapeutic intervention. Thiamine derivatives were analysed by high performance liquid chromatography in 106 whole blood and 38 cerebrospinal fluid samples from paediatric controls, 16 cerebrospinal fluid samples from patients with Leigh syndrome, six of whom harboured mutations in the SLC19A3 gene, and 49 patients with other neurological disorders. Free-thiamine was remarkably reduced in the cerebrospinal fluid of five SLC19A3 patients before treatment. In contrast, free-thiamine was slightly decreased in 15.2% of patients with other neurological conditions, and above the reference range in one SLC19A3 patient on thiamine supplementation. We also observed a severe deficiency of free-thiamine and low levels of thiamine diphosphate in fibroblasts from SLC19A3 patients. Surprisingly, pyruvate dehydrogenase activity and mitochondrial substrate oxidation rates were within the control range. Thiamine derivatives normalized after the addition of thiamine to the culture medium. In conclusion, we found a profound deficiency of free-thiamine in the CSF and fibroblasts of patients with thiamine transporter-2 deficiency. Thiamine supplementation led to clinical improvement in patients early treated and restored thiamine values in fibroblasts and cerebrospinal fluid.

Folate is a B vitamin essential for brain metabolism. It participates in the de novo synthesis of purines and thymidine and, together with cobalamin, represents an important cofactor for homocysteine remethylation and S-adenosylmethionine production by the brain. As with other vitamin deficiency states, folate deficiency may be the consequence of acquired or inherited disorders. Several inborn errors of metabolism can lead to defective folate transport or impaired metabolism, resulting in systemic folate deficiency and, obligatorily, 5-methyltetrahydrofolate (5-MTHF) depletion in the nervous system detectable by assay of cerebrospinal fluid (CSF) levels.¹ Cerebral folate deficiency (CFD), however, is characterized by decreased concentrations of 5-MTHF in the CSF in the context of normal systemic folate metabolism.² The principal mechanistic hypothesis put forth for this condition implies defective transport of folate across the blood-CSF or blood-brain barriers.^3,4 Indeed, mutations in the FOLR1 gene (OMIM 136430), encoding the folate receptor α (FRα), can cause brain-specific folate transport deficiency leading to neurodegeneration in early childhood.⁵ In other patients with CFD, blocking autoantibodies against FRs may also play a pathogenic role.⁴