A rare case of adult onset LPIN1 associated rhabdomyolysis

doi:10.1016/j.nmd.2020.01.004

Neuromuscular Disorders

Volume 30, Issue 3, March 2020, Pages 241-245

https://doi.org/10.1016/j.nmd.2020.01.004 Get rights and content

Highlights

•
Adult onset metabolic myopathy due to compound heterozygous variants in LPIN1.
•
Next generation sequencing (NGS) identified compound heterozygous variants in LPIN1.
•
First detailed description of adult onset LPIN1 associated rhabdomyolysis.
•
Clinical differences between adult onset and those with childhood onset LPIN1 associated rhabdomyolysis.

Abstract

Pathogenic variants in LPIN1 are a recognised cause of severe and often fatal rhabdomyolysis in childhood. We present a rare case of adult onset recurrent rhabdomyolysis due to compound heterozygous variants in LPIN1. Despite first presenting with rhabdomyolysis in his twenties and having undergone extensive investigations, the patient did not receive a diagnosis until he was 46 years of age. DNA sequencing revealed a pathogenic deletion involving exon 18 of LPIN1 in conjunction with a c.2410G>A missense variant in exon 19. Whilst LPIN1 variants are a noteworthy cause of severe recurrent rhabdomyolysis in childhood, this is the first detailed description and only the second reported case of adult onset rhabdomyolysis. Variants in LPIN1 should be considered as a cause of recurrent severe rhabdomyolysis in adults when other more common causes have been excluded.

Introduction

LPIN1, located on chromosome 2p25.1, encodes lipin-1, an enzyme abundantly expressed in adipose tissue and muscle [1]. Lipin-1 acts as a phosphatidic acid phosphatase (PAP) catalysing the conversion of phosphatidic acid to diacylglycerol in the triacylglycerol synthesis pathway [2]. It is therefore an important enzyme in the biosynthesis of triglycerides and phospholipids. Lipin-1 also serves as a transcriptional coactivator, regulating expression of genes involved in fatty acid ß-oxidation and mitochondrial respiratory chain enzymes [3]. Deficiency of the gene product leads to impaired synthesis of phospholipids and accumulation of potentially harmful lyso-phospholipids in cells. Pathogenic variants in LPIN1 are a recognised cause of severe and often fatal rhabdomyolysis in childhood [1,4]. Presentation in adulthood is thought to be exceedingly rare, with only one case previously reported [5].

Section snippets

Case report

A 46-year-old man presented with a 25-year history of episodic myalgia and myoglobinuria. In his twenties, he complained of myalgia following exercise at the gym, involving a combination of aerobic exercise and lifting weights for up to an hour. Later, in his thirties, he suffered with recurrent episodes of proximal myalgia and myoglobinuria after working night shifts at a car manufacturing factory. His work involved strenuous manual tasks, but he often fasted when working a night shift and he

Discussion

Heterozygous variants in LPIN1 are second only to disorders of fatty acid oxidation as the commonest cause of severe recurrent rhabdomyolysis in children [1]. However, only one case of adult onset rhabdomyolysis due to LPIN1 variants has been reported [5]. Michot et al. reported an active man whose first bout of rhabdomyolysis occurred at 42 years in their case series. The previously described adult onset case was found to be compound heterozygous for the intragenic deletion in exon 18 seen in

References (13)

A. Zeharia et al.
Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood
Am J Hum Genet
(2008)
J. Donkor et al.
Three mammalian lipins act as phosphatidate phosphatases with distinct tissue expression patterns
J Biol Chem
(2007)
S. Richards et al.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology
Genet Med
(2015)
S.A. Jaradat et al.
Molecular analysis of LPIN1 in Jordanian patients with rhabdomyolysis
Meta Gene
(2016)
D. Nunes et al.
LPIN1 deficiency: a novel mutation associated with different phenotypes in the same family
Mol Genet Metab Rep
(2016)
I.A. Meijer et al.
LPIN1 deficiency with severe recurrent rhabdomyolysis and persistent elevation of creatine kinase levels due to chromosome 2 maternal isodisomy
Mol Genet Metab Rep
(2015)

There are more references available in the full text version of this article.

Cited by (8)

Hydroxychloroquine sulfate: A novel treatment for lipin-1 deficiency?
2023, Biomedicine and Pharmacotherapy
Lipin-1 deficiency is a life-threatening disease that causes severe rhabdomyolysis (RM) and chronic symptoms associated with oxidative stress. In the absence of treatment, Hydroxychloroquine sulfate (HCQ) was administered to patients off label use on a compassionate basis in order to improve their physical conditions.
Eleven patients with LPIN1 mutations were treated with HCQ. Clinical and biological efficacy and tolerance were assessed, including pain and quality of life, physical capacities, cardiopulmonary parameters, creatine kinase levels and plasma proinflammatory cytokines. To explore a dose-dependent effect of HCQ, primary myoblasts from 4 patients were incubated with various HCQ concentrations in growth medium (GM) or during starvation (EBSS medium) to investigate autophagy and oxidative stress.
Under HCQ treatment, patient physical capacities improved. Abnormal cardiac function and peripheral muscle adaptation to exercise were normalized. However, two patients who had the highest mean blood HCQ concentrations experienced RM. We hypothesized that HCQ exerts deleterious effects at high concentrations by blocking autophagy, and beneficial effects on oxidative stress at low concentrations. We confirmed in primary myoblasts from 4 patients that high in vitro HCQ concentration (10 µM) but not low concentration (1 µM and 0.1 µM) induced autophagy blockage by modifying endolysosomal pH. Low HCQ concentration (1 µM) prevented reactive oxygen species (ROS) and oxidized DNA accumulation in myoblasts during starvation.
HCQ improves the condition of patients with lipin-1 deficiency, but at low concentrations. In vitro, 1 µM HCQ decreases oxidative stress in myoblasts whereas higher concentrations have a deleterious effect by blocking autophagy.
Two tales of LPIN1 deficiency: from fatal rhabdomyolysis to favorable outcome of acute compartment syndrome
2022, Neuromuscular Disorders
Citation Excerpt :
Literature cohort showed that the median age at the first episode, and diagnosis was 25 months, and 6 years, respectively, with 1–10 acute attacks before diagnosis. LPIN1 deficiency is also described in adulthood [14,15]. Eight out of 73 patients in the literature were adults (Supplement-1).
LPIN1 deficiency is an autosomal recessive disease caused by biallelic mutations in LPIN1, where impaired fatty acid metabolism leads to stress in skeletal muscle, resulting in severe rhabdomyolysis, often triggered by fever, exercise, fasting, and anesthesia. It is the second most common cause of severe, recurrent episodes of rhabdomyolysis in early childhood which can result in serious morbidity and mortality. To date, 71 patients have been published in 20 clinical studies in the form of case series. We describe two previously unreported cases, one with a novel LPIN1 mutation that resulted in mortality, and another, to the best of our knowledge, with the first reported compartment syndrome managed with a favorable outcome in this disorder. Recognition of the complications including ventricular arrythmias, acute renal failure and compartment syndrome on the severe end of the spectrum may change the outcome and prognosis of this devastating condition.
First presentation of LPIN1 acute rhabdomyolysis in adolescence and adulthood
2020, Neuromuscular Disorders
Citation Excerpt :
Clinically patients present with episodes characterised by myalgia and myoglobinuria; creatine kinase (CK) increases over 100,000 UI/L but can reach 1 × 106 UI/L. Between episodes, clinical examination, CK and acyl-carnitine profile are usually normal [7]. To our knowledge, there has only been two reports of two individuals presenting with adult-onset rhabdomyolysis [6,8]. We describe two cases of LPIN1 mutation with a milder phenotype presenting in adolescence and adulthood respectively.
LPIN1 mutations are a known common cause of autosomal recessive, recurrent and life-threatening acute rhabdomyolysis of childhood-onset. The first episode of rhabdomyolysis usually happens in nearly all cases before the age of 5 and death is observed in 1/3 of patients. Here we present two cases of acute rhabdomyolysis with a milder phenotype caused by LPIN1 mutation presenting in adolescence (11 years old) and adulthood (40 years old) after Parvovirus infection and metabolic stress, respectively. In our opinion, the mutation types, epigenetic factors, the environment exposition to triggers or the existence of proteins with a similar structure of LPIN1, may have a role in modulating the onset of rhabdomyolysis. LPIN1 should be included on a panel of genes analysed in the investigation of adult individuals with rhabdomyolysis. Metabolic and viral stressors should be included in the list of possible rhabdomyolysis precipitant.
Systemic corticosteroids for the treatment of acute episodes of rhabdomyolysis in lipin-1-deficient patients
2023, Journal of Inherited Metabolic Disease
Acute recurrent rhabdomyolysis in a Chinese boy associated with a novel compound heterozygous LPIN1 variant: a case report
2021, BMC Neurology
Lipin 1 modulates mRNA splicing during fasting adaptation in liver
2021, JCI Insight

View all citing articles on Scopus

View full text

Article preview

Neuromuscular Disorders

Highlights

Abstract

Introduction

Section snippets

Case report

Discussion

References (13)

Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood

Am J Hum Genet

Three mammalian lipins act as phosphatidate phosphatases with distinct tissue expression patterns

J Biol Chem

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology

Genet Med

Molecular analysis of LPIN1 in Jordanian patients with rhabdomyolysis

Meta Gene

LPIN1 deficiency: a novel mutation associated with different phenotypes in the same family

Mol Genet Metab Rep

LPIN1 deficiency with severe recurrent rhabdomyolysis and persistent elevation of creatine kinase levels due to chromosome 2 maternal isodisomy

Mol Genet Metab Rep

Cited by (8)

Hydroxychloroquine sulfate: A novel treatment for lipin-1 deficiency?

Two tales of LPIN1 deficiency: from fatal rhabdomyolysis to favorable outcome of acute compartment syndrome

First presentation of LPIN1 acute rhabdomyolysis in adolescence and adulthood

Systemic corticosteroids for the treatment of acute episodes of rhabdomyolysis in lipin-1-deficient patients

Acute recurrent rhabdomyolysis in a Chinese boy associated with a novel compound heterozygous LPIN1 variant: a case report

Lipin 1 modulates mRNA splicing during fasting adaptation in liver

Case reportA rare case of adult onset LPIN1 associated rhabdomyolysis

Highlights

Abstract

Introduction

Section snippets

Case report

Discussion

Am J Hum Genet

J Biol Chem

Genet Med

Meta Gene

Mol Genet Metab Rep

Mol Genet Metab Rep

Case report
A rare case of adult onset LPIN1 associated rhabdomyolysis