A Case of Mitochondrial Myopathy, Lactic Acidosis and Sideroblastic Anemia (MLASA Syndrome) and Long QT Interval in a 10-Year-Old Saudi Child

Abstract

MLASA syndrome is a rare mitochondrial disorder that presents in three distinct genetic forms: MLASA1, MLASA2, and MLASA3; MLASA1 is the most common form. The clinical features include mitochondrial myopathy, lactic acidosis, and sideroblastic anemia. Although presence of other features is not uncommon, its association with long QT (LQT) syndrome has not been described before. In addition, while MLASA syndrome has been reported from several countries worldwide, we present the first patient with MLASA1 syndrome from the Kingdom of Saudi Arabia in this case report. The 10-year-old girl with history of poor health since infancy and recurrent hospital admissions for infections and blood transfusions was referred to our hospital for allogeneic bone marrow transplantation. Early in her childhood, she was diagnosed with symptomatic LQT syndrome and, at a later age, with sideroblastic anemia. Whole-exome sequencing (WES) revealed homozygous mutations in the PUS1 gene and heterozygous mutations in the KCNQ1 gene. The WES test of the parents was negative, and there was no family history suggestive of a similar diagnosis. Therefore, our patient has most probably developed the syndrome as a result of a sporadic de novo mutation; however, the possibility of sex cell germline mosaicism cannot be excluded. Heterozygous KCNQ1 gene mutation is associated with the development of type 1 LQT syndrome. Detection of the MLASA syndrome and proper intervention at an early age are crucial for successful management. Associated LQT syndrome should always be anticipated. Despite the presence of a fully tissue-matched sibling, the parents of our patient declined the option of allogeneic bone marrow transplantation due to potential severe cardiac and liver complications.

INTRODUCTION

Mitochondria are essential cytoplasmic organelles of all eukaryotic cells and play a crucial role in producing most of the cell’s energy through oxidative phosphorylation pathways.[1] Mitochondrial disorders in children and adults are deleterious and are commonly caused by nuclear and mitochondrial DNA mutations.[2] The MLASA1 syndrome (mitochondrial myopathy [MM], lactic acidosis [LA], and sideroblastic anemia [SA]) is the most common mitochondrial disorder. It primarily results from a homozygous mutation in the PUS1 gene (OMIM #600462), located on chromosome 12. The gene encodes for the pseudo-uridylate synthase 1, a nuclear and mitochondrial enzyme. The MLASA2 and MLASA3 syndromes are characterized by mutations in the YARS2 (OMIM #613561) and ATP6 (OMIM #500011) genes, respectively, which encode mitochondrial enzymes. Defects in those genes can lead to respiratory chain dysfunction by decreasing mitochondrial enzyme activity and reducing protein synthesis.[3,4]

The inheritance pattern of mitochondrial diseases is complex. They can be inherited through maternal inheritance (from the mother via mitochondrial DNA) or through nuclear DNA inheritance (autosomal recessive, autosomal dominant, or X-linked). Defect due to mitochondrial inheritance appear in every generation and affect all males and females. Some cases are due to sporadic new mutations, while others are recessively inherited. A rare case of MLASA syndrome resulting from a PUS1 gene mutation has been reported to have been caused by uniparental isodisomy of chromosome 12.[5] Genetic diagnosis of mitochondrial disorders can be reached using single gene sequencing, targeted mitochondrial gene panel, whole-exome sequencing (WES), mitochondrial genome sequencing, or whole genome sequencing.[6]

LA results from increased LA production in the liver or skeletal muscles. The usual common pathway for LA is the increased production of pyruvate or nicotinamide adenine dinucleotide (NADH) during oxidative phosphorylation.[4,7] The presence of LA indicates a defect in a major body system; primary causes include mitochondrial disorders and organic acidemias. If untreated, LA could result in severe metabolic derangement and potentially life-threatening complications. Chronic LA could result in muscle cramps, anorexia, and weakness.[7]

Cases of MLASA have been reported from various countries worldwide;[3,4,8] however, to the best of the authors’ knowledge, no such cases has previously been reported from Saudi Arabia. Here, we report the first case of MLASA from Saudi Arabia in a young girl.

CASE REPORT

A 10-year-old girl was referred to our hospital for allogeneic bone marrow transplantation (aBMT). She was born by spontaneous delivery via an uneventful pregnancy. Her parents are healthy, first cousins. The patient had three older healthy siblings. Her growth and development were normal until 9 months of age, when she started developing recurrent respiratory infections. She had an episode of near drowning at home at the age of 3 years, followed by an episode of syncope. She was diagnosed with congenital long QT (LQT) syndrome and was started on atenolol. She persisted in having short syncopal attacks, which necessitated cardiac sympathetic denervation. At the age of 7 years, she was diagnosed with SA and received frequent blood transfusions. She subsequently developed iatrogenic hemosiderosis and was started on oral deferasirox.

In our hospital, the child looked well, with no dysmorphic features but was pale. Her growth parameters were below the 3^rd percentile for age. Her systemic examination was otherwise normal, with no evidence of myopathy or organomegaly. Her hemoglobin level was 7.8 g/L. The MCV and MCH were normal. A blood smear showed a dimorphic blood picture. Hemoglobin electrophoresis showed a normal AA pattern. The bone marrow biopsy was consistent with SA. The serum ferritin was 3400 mcg/L (normal range: 13.7–78.5 mcg/L).

Computerized tomography scans of the chest, abdomen, and pelvis, as well as magnetic resonance imaging of the brain were all normal, except for mild hepatomegaly. Electrocardiogram (ECG) showed a normal heart axis, rate, and rhythm. The corrected Q-T interval was prolonged at 476 mS (normal: <456 mS). Echocardiogram showed normal cardiac structure and function. The liver, kidney function tests, and serum electrolytes were normal.

The serum bicarbonate level was 14 mmol/L (normal range: 17–26 mmol/L). The serum LA levels were high, ranging from 6 to 6.7 mmol/L (normal range: 0.7–2.0 mmol/L). The WES test revealed a homozygous PUS1 mutation, confirming the diagnosis of MLASA1 syndrome. The WES test results of both parents were normal. MRI of the liver showed mild hepatomegaly and severe iron overload. Cardiac MRI showed no excess iron deposition. The electromyogram (EMG) showed a myopathic pattern, with marginally reduced motor unit action potential size and duration. Muscle biopsy was deemed unnecessary by the neurologist. The child had a human leukocyte antigen fully matched sibling. Based on the patient’s clinical situation, aBMT, although curative for SA, was expected to carry significant complications. The parents were not prepared to take such risks and opted to continue with the standard care management.

DISCUSSION

In MLASA syndrome, the PUS1 gene mutation is associated with a deficiency in mitochondrial complex 1 (NADH dehydrogenase) and IV (cytochrome-c-oxidase) enzymes. The YARS2 mutation is associated with combined complex I and III (cytochrome c-oxidoreductase) deficiencies, while the ATP6 gene mutation is associated with complex V (ATP synthase) deficiency. This difference may account for the variability in the clinical presentation. Complex I, III, V, and IV are mitochondrial electron transport chain enzymes needed for ATP generation. Skeletal muscle biopsy in patients with myopathy reveal reduced complex I, III, and IV levels. As a result, patients often experience progressive skeletal muscle weakness and LA.[9,10]

MLASA syndrome affects almost every organ system. The clinical severity of the syndrome is variable. A phenotype–genotype correlation has been suggested, with the less common MLASA2 (YARS2 mutation) and MLASA3 (ATP6 mutation) syndromes being the accelerated forms.[2,8,11]

Early-onset disease is nearly always associated with a severe clinical course. Patients suffer from severe acid–base imbalance and progressive myopathy. Late-presenting patients may develop slowly progressive myopathy that takes several years to be recognized. LA and SA, however, may present at any time, from infancy to late childhood.[8,10] Here, we present a case of a girl with a late-onset, slowly progressive disease who suffered from chronic ill health and LQT syndrome. She was diagnosed with congenital SA at the age of 7 years. Despite the early myopathic EMG pattern, she had no clinical evidence of myopathy. The diagnosis of sporadic MLASA1 syndrome was only made at the age of 10 years following genetic testing.

Congenital LQT syndrome is a serious cardiac conduction defect characterized by prolongation of the action potentials, causing serious arrhythmias. More than 50% of patients have a homozygous mutation in the KCNQ1 gene, which encodes potassium ion transport channels.[12]

The association of cardiac abnormalities with MLASA syndrome is not common, with hypertrophic cardiomyopathy being the most prevalent. Burrage et al. reported a 6-year-old child with MLASA syndrome due to MTATP6 gene mutation who developed Wolff–Parkinson–White syndrome. No clear genetic link was found, but the cause could have been related to MM.[8]

Our patient was diagnosed with symptomatic LQT1 syndrome in early childhood. Congenital LQT1 syndrome has never been reported in association with MLASA syndrome. The WES test revealed a heterozygous mutation of the KCNQ1 gene. Heterozygous KCNQ1 gene mutation is associated with the development of type 1, LQT syndrome. The relationship between the heterozygous KCNQ1 gene mutation on chromosome 11 and the PUS1 gene mutation on chromosome 12 is unclear. However, both syndromes could be recessively inherited. As a result of consanguineous marriage, in rare occasions, a patient may have two coexistent genetically inherited disorders. Our patient initially responded well to atenolol but subsequently required selective cardiac sympathetic denervation.

Congenital SA is one of the main features of MLASA syndrome. The genetic basis of SA can be identified in >50% of patients. MLASA syndrome-associated SA is directly caused by defects in the PUS1, YARS2, and ATP6 genes.[4,8] aBMT is the only known curative treatment for congenital SA and may benefit patients with mitochondrial MLASA syndrome. BMT is associated with potentially severe complications; however, the benefits may outweigh the risks.[11,13]

Mitochondrial disorders are an area of active research. Mitochondrial transplantation is a new technique being developed using donor hematopoietic stem cells. Mitochondrial transplantation has been shown to rescue aerobic respiration in mouse models. The procedure has many similarities to autologous BMT. Although many aspects remain unclear, the literature suggests a potential role for mitochondrial transplantation in providing a cure.[2,14]

Our patient had a fully HLA-matched sibling. Despite the expected high risk of complications, we were prepared to proceed with the matched sibling BMT procedure using reduced-intensity conditioning. If successful, aBMT is considered to cure congenital SA.[13] Whether aBMT will also cure MLASA syndrome is unknown, as no previous reports indicating such benefit were found. However, the parents denied aBMT and preferred to continue with standard management.

CONCLUSION

MLASA syndromes should always be considered in patients with SA and/or LA and relevant genetic testing should be performed. Patients should undergo EMG and ECG to assess associated myopathy and LQT syndrome. Early diagnosis and initiation of the appropriate management may help prevent fatal complications.

Declaration of patient consent

The authors certify that the appropriate patient consent form has been obtained. In the form, the patient’s father has given consent for his daughter’s clinical information to be reported in the journal. The patient’s father understands that her name and initials will not be published, and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.

Ethical considerations

Ethical approval for reporting the case was obtained from Institutional Review Board of King Abdullah International Medical Research Center, Riyadh, Saudi Arabia (Approval no.: 00000154725; date: May 08, 2025)

Peer review

This case report was peer-reviewed by two independent and anonymous reviewers.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.