Hyperphosphatasia with mental retardation syndrome 3: Cerebrospinal fluid abnormalities and correction with pyridoxine and Folinic acid.

Glycosylphosphatidylinositol anchored proteins (GPI-APs) represent a class of molecules attached to the external leaflet of the plasma membrane by the GPI anchor where they play important roles in numerous cellular processes including neurogenesis, cell adhesion, immune response and signalling. Within the group of GPI anchor defects, six present with the clinical phenotype of Hyperphosphatasia with Mental Retardation Syndrome (HPMRS, Mabry Syndrome) characterized by moderate to severe intellectual disability, dysmorphic features, hypotonia, seizures and persistent hyperphosphatasia. We report the case of a 5-year-old female with global developmental delay associated with precocious puberty and persistently raised plasma alkaline phosphatase. Targeted next generation sequencing analysis of the HPMRS genes identified novel compound heterozygous variants in the PGAP2 gene (c.103del p.(Leu35Serfs*90)and c.134A > Gp.(His45Arg)) consistent with the diagnosis of HPMRS type 3. Cerebrospinal fluid (CSF) neurotransmitter analysis showed low levels of pyridoxal phosphate and 5-methyltetrahydrofolate and raised homovanillic acid. Supplementation with pyridoxine and folinic acid led to normalization of biochemical abnormalities. The patient continues to make developmental progress with significant improvement in speech and fine motor skills. Our reported case expands the clinical spectrum of HPMRS3 in which multisystem involvement is being increasingly recognized. Furthermore, it shows that miss-targeting GPI-APs and the effect on normal cellular function could provide a physiopathologic explanation for the CSF biochemical abnormalities with management implications for a group of disorders that currently has no treatment that can lead possibly to improved clinical outcomes.

A step closer in defining glycosylphosphatidylinositol anchored proteins role in health and glycosylation disorders.

Glycosylphosphatidylinositol anchored proteins (GPI-APs) represent a class of soluble proteins attached to the external leaflet of the plasma membrane by a post-translation modification, the GPI anchor. The 28 genes currently involved in the synthesis and remodelling of the GPI anchor add to the ever-growing class of congenital glycosylation disorders. Recent advances in next generation sequencing technology have led to the discovery of Mabry disease and CHIME syndrome genetic aetiology. Moreover, with each described mutation known phenotypes expand and new ones emerge without clear genotype-phenotype correlation. A protein database search was made for human GPI-APs with defined pathology to help building-up a physio-pathological mechanism from a clinical perspective. GPI-APs function in vitamin-B6 and folate transport, nucleotide metabolism and lipid homeostasis. Defining GPI-APs role in disease bears significant clinical implications.

Role of Intramuscular Levofolinate Administration in the Treatment of Hereditary Folate Malabsorption: Report of Three Cases.

Hereditary folate malabsorption is a rare autosomal recessive disorder caused by impaired active folate transport across membranes and into the central nervous system due to loss-of-function mutations in proton-coupled folate transporter (PCFT). Newborns with this condition have initially normal folate stores, but as they are unable to absorb dietary folate and use rapidly their stores because of their growth demands, symptoms appear in the early infancy. Significant neurological morbidity usually follows the initial non-specific clinical presentation and delayed initiation of treatment. High dose oral and parenteral folinic acid treatment have been previously reported in literature to improve the clinical outcome without achieving optimal cerebrospinal fluid (CSF) folate levels though. The active isomer of 5-formyltetrahydrofolate, also known as levofolinic acid, is available for administration. We report our experience in achieving normal (age dependent) CSF 5-Methyltetrahydrofolate (5-MTHF) levels following daily intramuscular administration of levofolinic acid in three patients with HFM. Follow-up assessment with repeated lumbar punctures has shown a stabilization of 5-MTHF levels within normal range. Clinical features and brain MRI findings had as well either improvement or stabilization. To the best of our knowledge, we provide as well for the first time data in regard to the im levofolinate treatment dosage.