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

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.

Stroke-like Episodes in Inherited Neurometabolic Disorders

“…The presented mutation leads to hypoglycosylation of the α1A and α2α CaV2.1 channel subunits. A similar genetic alteration could also be observed in patients with ataxia and Familial Hemiplegic Migraine (FMH), the paroxysmal neurological disorder connected with mutations in ion transporters: CACNA1A that encodes the alpha 1A subunit of CaV2.1 voltage-gated channel [ 92 , 93 , 94 , 95 ]. Other mutations associated with FHM include ATP1A2, which encodes the alpha2 subunit of Na + , K + -ATPase pump or SCN1A (responsible for encoding the NaV1.1 channel alpha1 subunit).…”

“…The most common congenital disorder of glycosylation is phosphomannomutase 2 deficiency (PMM2-CDG), which is characterized by chronic cerebellar atrophy as the most frequent clinical manifestation. Other clinical features include migraine, epileptic seizures and SLEs [ 91 , 92 , 93 , 94 ]. Secondary to the atrophy of the cerebellum, patients develop ataxia; PMM2-CDG is associated with the CACNA1A gene gain-of-function mutation that encodes the voltage-gated CaV2.1 channel [ 93 , 94 ].…”

“…Other clinical features include migraine, epileptic seizures and SLEs [ 91 , 92 , 93 , 94 ]. Secondary to the atrophy of the cerebellum, patients develop ataxia; PMM2-CDG is associated with the CACNA1A gene gain-of-function mutation that encodes the voltage-gated CaV2.1 channel [ 93 , 94 ]. The presented mutation leads to hypoglycosylation of the α1A and α2α CaV2.1 channel subunits.…”

“…Ataxia in PMM2 CDG disorder is connected with the hypoglycosylation of the alpha-beta-δ subunit and leads to the opening of the CaV2.1 voltage-gated channel. According to studies, there are no significant genetic differences in patients with PMM2 CDG who are affected by SLE in comparison to ones who do not suffer from this clinical manifestation [ 93 , 94 , 97 ]. As a consequence of the unspecificity of SLE clinical manifestations, EEG results and radiological and laboratory test findings, there is a requirement to create specific investigation models to improve the whole diagnostic process.…”

Patient reported outcomes for phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG): listening to what matters for the patients and health professionals

“…Other neurological occurrences were also prioritized with lower impact scores, namely seizures and stroke-like episodes. These are mainly rare clinical events reported to happen in 13% and 7% of patients, respectively, but have been described as some of the most QoL-impacting issues in PMM2-CDG [ 13 , 29 , 30 ]. Surprisingly, much more pronounced impact scores are suggested by clinicians compared to families concerning these neurological manifestations.…”