Stroke-Like Episodes in PMM2-CDG: When the Lack of Other Evidence Is the Only Evidence.

Mercedes Serrano

doi:10.3389/fped.2021.717864

Abstract

Phosphomannomutase 2 deficiency (PMM2-CDG) is the most frequent congenital disorder of glycosylation. PMM2-CDG patients develop chronic cerebellar atrophy as a neurological hallmark. However, other acute neurological phenomena such as stroke-like episodes (SLE), epilepsy, migraine, and cerebrovascular events, may also occur, and they are frequently the cause of disability and impaired quality of life. Among these, SLE are among the most stressful situations for families and doctors, as their risk factors are not known, their underlying pathomechanisms remain undiscovered, and clinical guidelines for diagnosis, prevention, and treatment are lacking. In this paper, the recent SLE experiences of two PMM2-CDG patients are examined to provide clinical clues to help improve diagnosis through a clinical constellation of symptoms and a clinical definition, but also to support a neuroelectrical hypothesis as an underlying mechanism. An up-to-date literature review will help to identify evidence-based and non-evidence-based management recommendations. Presently neuropediatricians and neurologists are not capable of diagnosing stroke-like episodes in an unequivocal way, so there is still a need to perform invasive studies (to rule out other acute diseases) that may, in the end, prove unnecessary or even harmful. However, reaching a correct and early diagnosis would lead not only to avoidance of invasive tests but also to better recognition, management, and understanding of the disease itself. There is a great need for understanding of SLE that may ultimately be very informative for the detection of patients at risk, and the future development of preventive and management measures.

Highlights

Congenital disorders of glycosylation (CDG) are a rapidly expanding group of metabolic disorders with defects in the synthesis of glycans and their attachment to proteins and lipids
This is the case of PMM2-CDG and some channelopathies related to CACNA1A, ATP1A2, and SCN1A mutations, leading to episodes called familial hemiplegic migraine (FHM)
FHM is, very similar clinically to stroke-like episodes (SLE), as episodes are triggered by metabolic stress or cranial trauma, they present after a symptomfree period, and they progress to irritability, somnolence, focal deficits with hyperpyrexia, and, frequently epileptic seizures, eventually ending in clinical resolution after a period of time from hours to days [8, 12, 15, 16]

Summary

INTRODUCTION

Congenital disorders of glycosylation (CDG) are a rapidly expanding group of metabolic disorders with defects in the synthesis of glycans and their attachment to proteins and lipids. The term SLE was initially coined for MELAS syndrome to stress its non-ischemic origin [14] but it has been used for different neurological diseases associated with focal deficits that mimick, clinically but not neuroradiologically, an ischemic injury This is the case of PMM2-CDG and some channelopathies related to CACNA1A, ATP1A2, and SCN1A mutations, leading to episodes called familial hemiplegic migraine (FHM). FHM is, very similar clinically to SLE, as episodes are triggered by metabolic stress or cranial trauma, they present after a symptomfree period, and they progress to irritability, somnolence, focal deficits with hyperpyrexia, and, frequently epileptic seizures, eventually ending in clinical resolution after a period of time from hours to days [8, 12, 15, 16] These clinical resemblances may correspond to common biological disturbances, as was recently demonstrated through the experimental generation of impaired N-glycosylation at the CaV2.1 (encoded by CACNA1A); impaired N-glycosylation led to a gain-of-function on the CaV2.1 channel [8], similar to those mutations causing FHM [17, 18]. A literature review will help to identify evidence-based management recommendations, and the vascular and neuroelectrical hypotheses will be discussed as potential underlying mechanisms in SLE

METHOD

DISCUSSION

Findings

ETHICS STATEMENT