Inherited Neuromuscular Disorders: Which Role for Serum Biomarkers?

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Abstract

Inherited neuromuscular disorders (INMD) are a heterogeneous group of rare diseases that involve muscles, motor neurons, peripheral nerves or the neuromuscular junction. Several different lab abnormalities have been linked to INMD: sometimes they are typical of the disorder, but they usually appear to be less specific. Sometimes serum biomarkers can point out abnormalities in presymtomatic or otherwise asymptomatic patients (e.g., carriers). More often a biomarker of INMD is evaluated by multiple clinicians other than expert in NMD before the diagnosis, because of the multisystemic involvement in INMD. The authors performed a literature search on biomarkers in inherited neuromuscular disorders to provide a practical approach to the diagnosis and the correct management of INMD. A considerable number of biomarkers have been reported that support the diagnosis of INMD, but the role of an expert clinician is crucial. Hence, the complete knowledge of such abnormalities can accelerate the diagnostic workup supporting the referral to specialists in neuromuscular disorders.

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Evidence-based path to newborn screening for Duchenne muscular dystrophy.

Jerry R Mendell, Chris Shilling, Nancy D Leslie … (2012)

Creatine kinase (CK) levels are increased on dried blood spots in newborns related to the birthing process. As a marker for newborn screening, CK in Duchenne muscular dystrophy (DMD) results in false-positive testing. In this report, we introduce a 2-tier system using the dried blood spot to first assess CK with follow-up DMD gene testing. A fluorometric assay based upon the enzymatic transphosphorylation of adenosine diphosphate to adenosine triphosphate was used to measure CK activity. Preliminary studies established a population-based range of CK in newborns using 30,547 deidentified anonymous dried blood spot samples. Mutation analysis used genomic DNA extracted from the dried blood spot followed by whole genome amplification with assessment of single-/multiexon deletions/duplications in the DMD gene using multiplex ligation-dependent probe amplification. DMD gene mutations (all exonic deletions) were found in 6 of 37,649 newborn male subjects, all of whom had CK levels>2,000U/l. In 3 newborns with CK>2,000U/l in whom DMD gene abnormalities were not found, we identified limb-girdle muscular dystrophy gene mutations affecting DYSF, SGCB, and FKRP. A 2-tier system of analysis for newborn screening for DMD has been established. This path for newborn screening fits our health care system, minimizes false-positive testing, and uses predetermined levels of CK on dried blood spots to predict DMD gene mutations. Copyright © 2012 American Neurological Association.

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Carnitine transport and fatty acid oxidation.

Nicola Longo, Marta Frigeni, Marzia Pasquali (2016)

Carnitine is essential for the transfer of long-chain fatty acids across the inner mitochondrial membrane for subsequent β-oxidation. It can be synthesized by the body or assumed with the diet from meat and dairy products. Defects in carnitine biosynthesis do not routinely result in low plasma carnitine levels. Carnitine is accumulated by the cells and retained by kidneys using OCTN2, a high affinity organic cation transporter specific for carnitine. Defects in the OCTN2 carnitine transporter results in autosomal recessive primary carnitine deficiency characterized by decreased intracellular carnitine accumulation, increased losses of carnitine in the urine, and low serum carnitine levels. Patients can present early in life with hypoketotic hypoglycemia and hepatic encephalopathy, or later in life with skeletal and cardiac myopathy or sudden death from cardiac arrhythmia, usually triggered by fasting or catabolic state. This disease responds to oral carnitine that, in pharmacological doses, enters cells using the amino acid transporter B(0,+). Primary carnitine deficiency can be suspected from the clinical presentation or identified by low levels of free carnitine (C0) in the newborn screening. Some adult patients have been diagnosed following the birth of an unaffected child with very low carnitine levels in the newborn screening. The diagnosis is confirmed by measuring low carnitine uptake in the patients' fibroblasts or by DNA sequencing of the SLC22A5 gene encoding the OCTN2 carnitine transporter. Some mutations are specific for certain ethnic backgrounds, but the majority are private and identified only in individual families. Although the genotype usually does not correlate with metabolic or cardiac involvement in primary carnitine deficiency, patients presenting as adults tend to have at least one missense mutation retaining residual activity. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.

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Types A and B Niemann-Pick disease.

Edward Schuchman, Robert J Desnick (2017)

The eponym Niemann-Pick disease (NPD) refers to a group of patients who present with varying degrees of lipid storage and foam cell infiltration in tissues, as well as overlapping clinical features including hepatosplenomegaly, pulmonary insufficiency and/or central nervous system (CNS) involvement. Due to the pioneering work of Roscoe Brady and co-workers, we now know that there are two distinct metabolic abnormalities that account for NPD. The first is due to the deficient activity of the enzyme acid sphingomyelinase (ASM; "types A & B" NPD), and the second is due to defective function in cholesterol transport ("type C" NPD). Herein only types A and B NPD will be discussed. Type A NPD patients exhibit hepatosplenomegaly in infancy and profound CNS involvement. They rarely survive beyond 2-3years of age. Type B patients also have hepatosplenomegaly and pathologic alterations of their lungs, but there are usually no CNS signs. The age of onset and rate of disease progression varies greatly among type B patients, and they frequently live into adulthood. Intermediate patients also have been reported with mild to moderate neurological findings. All patients with types A and B NPD have mutations in the gene encoding ASM (SMPD1), and thus the disease is more accurately referred to as ASM deficiency (ASMD). Herein we will review the clinical, pathological, biochemical, and genetic findings in types A and B NPD, and emphasize the seminal contributions of Dr. Brady to this disease. We will also discuss the current status of therapy for this disorder.

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Author and article information

Contributors

Boel De Paepe: Role: Academic Editor

Marcello Ciaccio: Role: Academic Editor

Journal

Journal ID (nlm-ta): Brain Sci

Journal ID (iso-abbrev): Brain Sci

Journal ID (publisher-id): brainsci

Title: Brain Sciences

Publisher: MDPI

ISSN (Electronic): 2076-3425

Publication date (Electronic): 21 March 2021

Publication date Collection: March 2021

Volume: 11

Issue: 3

Electronic Location Identifier: 398

Affiliations

Department of Biomedicine, Neuroscience and advanced Diagnostic (BIND), University of Palermo, 90121 Palermo, Italy; vincenzo19689@ 123456gmail.com (V.D.S.); andrigl@ 123456gmail.com (A.G.); salvo.iak@ 123456gmail.com (S.I.); niettapignolo@ 123456gmail.com (A.P.); fransalvo1@ 123456gmail.com (S.F.); angelotorrente92@ 123456gmail.com (A.T.); sonia.pagano@ 123456policlinico.pa.it (S.P.); massimo.gangitano@ 123456unipa.it (M.G.); filippobrighina@ 123456gmail.com (F.B.)

Author notes

[* ]Correspondence: antlupica@ 123456gmail.com

Author information

Antonino Lupica https://orcid.org/0000-0003-1499-9460

Vincenzo Di Stefano https://orcid.org/0000-0001-9805-1655

Salvatore Iacono https://orcid.org/0000-0003-0035-5859

Antonia Pignolo https://orcid.org/0000-0002-8883-5701

Angelo Torrente https://orcid.org/0000-0002-0585-8351

Article

Publisher ID: brainsci-11-00398

DOI: 10.3390/brainsci11030398

PMC ID: 8004068

SO-VID: d001a595-0255-40d9-9223-4028f327d985

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Inherited Neuromuscular Disorders: Which Role for Serum Biomarkers?

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Abstract

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Journal of Circulating Biomarkers

Most cited references 183

Evidence-based path to newborn screening for Duchenne muscular dystrophy.

Carnitine transport and fatty acid oxidation.

Types A and B Niemann-Pick disease.

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