Nemaline Rods and Complex I Deficiency in Three Infants with Hypotonia, Motor Delay and Failure to Thrive

Lamont, Phillipa; Thorburn, David R.; Fabian, V.; Vajsar, Jiri; Hawkins, Cynthia; Saada, Ann; Durling, Hayley J.; Laing, Nigel G.; Nevo, Yoram

doi:10.1055/s-2004-821243

Cited by 21 publications

(11 citation statements)

References 13 publications

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“…Rods can be a secondary response to metabolic stress. Numerous rods were observed in a few patients with Complex I deficiency (Lamont et al 2004) and in both muscle and non-muscle cells in vitro, they can be induced by a variety of substances that cause energy shortage, including ATP depletion and heat shock proteins (Vandebrouck et al 2010). This in vitro study suggested that rods formed under different conditions vary with regard to their cofilin and α-actinin content.…”

Section: What Is a Nemaline Rod?mentioning

confidence: 99%

Nemaline myopathies: a current view

Sewry

Laitila

Wallgren‐Pettersson

2019

J Muscle Res Cell Motil

140

133

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Nemaline myopathies are a heterogenous group of congenital myopathies caused by de novo, dominantly or recessively inherited mutations in at least twelve genes. The genes encoding skeletal α-actin (ACTA1) and nebulin (NEB) are the commonest genetic cause. Most patients have congenital onset characterized by muscle weakness and hypotonia, but the spectrum of clinical phenotypes is broad, ranging from severe neonatal presentations to onset of a milder disorder in childhood. Most patients with adult onset have an autoimmune-related myopathy with a progressive course. The wide application of massively parallel sequencing methods is increasing the number of known causative genes and broadening the range of clinical phenotypes. Nemaline myopathies are identified by the presence of structures that are rod-like or ovoid in shape with electron microscopy, and with light microscopy stain red with the modified Gömöri trichrome technique. These rods or nemaline bodies are derived from Z lines (also known as Z discs or Z disks) and have a similar lattice structure and protein content. Their shape in patients with mutations in KLHL40 and LMOD3 is distinctive and can be useful for diagnosis. The number and distribution of nemaline bodies varies between fibres and different muscles but does not correlate with severity or prognosis. Additional pathological features such as caps, cores and fibre type disproportion are associated with the same genes as those known to cause the presence of rods. Animal models are advancing the understanding of the effects of various mutations in different genes and paving the way for the development of therapies, which at present only manage symptoms and are aimed at maintaining muscle strength, joint mobility, ambulation, respiration and independence in the activities of daily living.

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Section: What Is a Nemaline Rod?mentioning

confidence: 99%

Nemaline myopathies: a current view

Sewry

Laitila

Wallgren‐Pettersson

2019

J Muscle Res Cell Motil

140

133

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“…Ragged red fibres are not usually observed in nuclear-encoded complex I defects but were reported in single cases with NDUFS4 , NDUFS7 , FOXRED1 and NUBPL mutations 32 52 72. In addition, occasional patients with nemaline rods and complex I deficiency have been reported,73 and in one of these cases mutations of the structural subunit NDUFB3 were identified recently 74…”

Section: Approaches To Diagnosismentioning

confidence: 99%

Complex I deficiency: clinical features, biochemistry and molecular genetics

Fassone

Rahman²

2012

J Med Genet

270

257

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Complex I deficiency is the most frequent mitochondrial disorder presenting in childhood, accounting for up to 30% of cases. As with many mitochondrial disorders, complex I deficiency is characterised by marked clinical and genetic heterogeneity, leading to considerable diagnostic challenges for the clinician, not least because of the involvement of two genomes. The most prevalent clinical presentations include Leigh syndrome, leukoencephalopathy and other early-onset neurodegenerative disorders; fatal infantile lactic acidosis; hypertrophic cardiomyopathy; and exercise intolerance. Causative genetic defects may involve the seven mitochondrial-encoded or 38 nuclear-encoded subunits of the enzyme, or any of an increasing number of assembly factors implicated in the correct biosynthesis of complex I within the inner mitochondrial membrane. In this review, we discuss recent advances in knowledge of the structure, function and assembly of complex I and how these advances, together with new high-throughput genetic screening techniques, have translated into improved genetic diagnosis for affected patients and their families. Approximately 25% of cases have mitochondrial DNA mutations, while a further ∼25% have mutations in a nuclear subunit or in one of nine known assembly factors. We also present a systematic review of all published cases of nuclear-encoded complex I deficiency, including 117 cases with nuclear subunit mutations and 55 with assembly factor mutations, and highlight clinical, radiological and biochemical clues that may expedite genetic diagnosis.

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“… * The second mutation awaits identification, 1 published by Anderson et al (2004), ¤ Patient 6 was described by Lamont and co-workers in 2004 [6] …”

Section: Tablementioning

confidence: 99%

The exon 55 deletion in the nebulin gene – One single founder mutation with world-wide occurrence

Lehtokari

Greenleaf

DeChene

et al. 2009

Neuromuscular Disorders

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Anderson and co-workers (2004) reported a homozygous 2,502 bp deletion including exon 55 of the nebulin gene in five Ashkenazi Jewish probands with nemaline myopathy (NM) [1]. We determined the occurrence of this deletion in a world-wide series of 355 NM probands with no previously known mutation in other genes and found the mutation in 14 probands. Two of the families were not of known Ashkenazi Jewish descent but they had the haplotype known to segregate with this mutation. In all but two of eight homozygous patients, the clinical picture was more severe than in typical NM.

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Nemaline Rods and Complex I Deficiency in Three Infants with Hypotonia, Motor Delay and Failure to Thrive

Cited by 21 publications

References 13 publications

Nemaline myopathies: a current view

Nemaline myopathies: a current view

Complex I deficiency: clinical features, biochemistry and molecular genetics

The exon 55 deletion in the nebulin gene – One single founder mutation with world-wide occurrence

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