Two Siblings with LRPPRC Mutation: Mitochondrial Complex IV Deficiency: Case Report

Abstract

Introduction

Mitochondrial diseases caused by mutations in the LRPPRC gene are rare and lead to multisystemic dysfunction. We report two siblings from consanguineous Iraqi parents, both harboring a rare homozygous deletion in LRPPRC (c.2726_2728del; p.Lys909del), previously reported in one other patient. These cases contribute to the expanding phenotypic and geographic spectrum of LRPPRC-related mitochondrial disease.

Case Presentation

The younger sibling, a 9-year-old girl, presented with severe growth retardation, global developmental delay, hypotonia, spastic ataxic gait, and lactic acidosis. Magnetic resonance imaging showed symmetrical hyperintensities in the mesencephalon and thalami, cerebellar atrophy, and an inverted lactate peak on spectroscopy. Hypertrophic cardiomyopathy was also detected. The older sibling, aged 13, exhibited milder manifestations, including axial hypotonia, tremor, ataxia, and persistent hyperlactatemia. Both siblings had elevated lactate levels but otherwise normal metabolic panels. Whole exome sequencing revealed a homozygous mutation in the LRPPRC gene (c.2726_2728del; p.Lys909del) in both patients.

Conclusions

These cases highlight the clinical variability of LRPPRC-related disorders. Our report underscores the importance of considering LRPPRC mutations in the differential diagnosis of early-onset neurodevelopmental delay and multisystemic dysfunction with lactic acidosis, especially in populations with high rates of consanguinity. Early genetic diagnosis via whole exome sequencing is essential for accurate diagnosis, genetic counseling, and family planning.

Established Facts

• Mitochondrial disease due to LRPPRC mutations should be considered in patients with early-onset neurodevelopmental delay, persistent lactic acidosis, and multisystemic features.

• The same LRPPRC mutation can present with markedly different clinical phenotypes.

Novel Insights

• We report two siblings with mitochondrial complex IV deficiency due to a rare homozygous LRPPRC mutation (c.2726_2728del; p.Lys909del). To the best of our knowledge, these are the thirteenth and fourteenth reported cases with LRPPRC mutations outside the Saguenay-Lac-Saint-Jean region.

• Our cases contribute to expanding the phenotypic spectrum as well as the geographic and ethnic diversity of LRPPRC-related mitochondrial disease and highlight significant intrafamilial variability in clinical severity and neuroimaging findings.

Introduction

Mitochondrial oxidative phosphorylation (OXPHOS) is the primary process by which cells generate adenosine triphosphate (ATP), which is essential for energy-demanding tissues such as the brain, muscles, and heart. Defects in the mitochondrial respiratory chain, particularly involving complex IV (cytochrome c oxidase [COX]), have been demonstrated to result in a wide spectrum of multisystemic disorders. COX deficiency is among the most frequently reported mitochondrial defects and can manifest with Leigh syndrome, hepatic dysfunction, cardiomyopathy, and severe metabolic acidosis, especially in early childhood [1–3].

A rare nuclear etiology that results in isolated COX deficiency is the presence of a mutation in the LRPPRC gene. LRPPRC encodes a protein that plays a critical role in the post-transcriptional regulation of mitochondrial gene expression, particularly in the stabilization and translation of mitochondrial mRNAs necessary for the production of complex IV subunits [4]. The genetic variations in this gene have been demonstrated to result in a reduction of mitochondrial mRNA stability, which consequently leads to impaired COX assembly and subsequent OXPHOS dysfunction. A founder mutation in LRPPRC, well-documented in the scientific literature, has been identified as the causative agent of the French-Canadian variant of Leigh syndrome, a condition that is predominantly observed in the Saguenay-Lac-Saint-Jean region of Québec. As indicated in the following references, which are listed in order of their respective [3, 5–7].

Beyond this founder population, LRPPRC mutations have been increasingly reported in ethnically diverse families with similar phenotypes, often with early-onset neurodevelopmental regression, lactic acidosis, hypotonia, feeding difficulties, and cardiomyopathy. A study by Oláhová et al. described patients from Pakistani, Indian, Turkish, Iraqi, and Caucasian backgrounds harboring homozygous or compound heterozygous LRPPRC mutations, including a rare variant c.2726_2728del (p.Lys909del), previously reported in only one Iraqi patient. Here, we describe two Iraqi sisters born to consanguineous parents, both harboring the same rare homozygous c.2726_2728del mutation in LRPPRC, to highlight the clinical significance and raise awareness of this rare mitochondrial disorder beyond the founder population.

Case Presentation

Case 1

A 9-year-old female patient, the second of two siblings born to consanguineous Iraqi parents, was referred for evaluation of hypotonia, failure to thrive, developmental delay, ataxic gait, tremor, and persistent hyperlactatemia. She was delivered at term via an emergency cesarean section procedure due to fetal distress. No dysmorphic features were observed during the neonatal examination.

She was diagnosed with congenital adrenal hyperplasia due to 21-hydroxylase deficiency shortly after birth and has since been treated with hydrocortisone and fludrocortisone. The presence of global developmental delay was first observed at 24 months of age. By the age of 4, the patient exhibited symptoms of hypotonia, characterized by a reduced muscle tone and decreased mobility. Additionally, she demonstrated a wide-based ataxic gait, indicating a loss of coordination and equilibrium, accompanied by tremor in the distal limbs, affecting the hands and feet.

A physical examination at the age of 9 years revealed severe growth failure (weight = 15 kg; standard deviation score [SDS] = −3.5) and a height of 103 cm (SDS = −4.37). The subject also presented with a cachectic physique, ambiguously delineated genitalia (Prader grade 5), and numerous café au lait macules. Her verbal expression was limited to brief utterances, and she required assistance with ambulation. A neurological examination was conducted, which revealed the following findings: hyperreflexia of the lower extremities, dysmetria, postural tremor, spasticity, and intermittent titubation. Additionally, deep tendon reflexes were found to be brisk, particularly in the legs. The patient's gait exhibited characteristics of a broad base, spasticity, and ataxia, manifesting as a pronounced medial longitudinal arch. Psychiatric and ophthalmologic assessments confirmed global developmental delay and refractive error, respectively. She has a prominent forehead and arched eyebrows (Fig. 1a).

Fig. 1.

a Case 1 has a prominent forehead and arched eyebrows. b There was no significant craniofacial dysmorphism in Case 2; she only has arched eyebrows. c Pedigree of the family.

In the laboratory assessment, the complete blood count, renal and hepatic panels, creatine kinase, and serum electrolytes were unremarkable. However, serum lactate levels were found to be markedly elevated at 46.3 mmol/L (reference range [RR]: 0.5–2.2), accompanied by a concomitant pyruvate level of 1.3 mg/dL (RR: 0.3–0.9). A normal range of carnitine-acyl carnitine levels and plasma amino acid profiles was observed; however, urinary organic acid analysis revealed elevated levels of 4-hydroxypyruvic acid (3.31 mmol/mol creatinine, RR: 0–0.3). The occurrence of episodes of lactic acidosis and metabolic decompensation was precipitated by the presence of concomitant infections.

Transthoracic echocardiography revealed hypertrophic cardiomyopathy (HCM); left ventricular mass index = 49 g/m^2.7 (>Pmax: 44.3 g/m^2.7). Cranial magnetic resonance imaging (MRI) and MR spectroscopy revealed symmetrical hyperintense signal changes on T2-weighted and FLAIR sequences in the tectal region of the mesencephalon and medial thalami, with central cavitation-like areas. The cerebellar folia appeared widened, consistent with cerebellar atrophy. Multiple nonspecific T2/FLAIR hyperintense foci were also noted in the subcortical white matter of the bifrontal and biparietal regions. Mid-echo MR spectroscopy at the thalamic level demonstrated an inverted lactate peak (Fig. 2). These findings are suggestive of primary mitochondrial disease involvement. A comprehensive electroencephalography evaluation yielded normal results.

Fig. 2.

a–c Brain MRI shows cerebellar atrophy (asterisks) and symmetric hyperintensity with cavitation in the thalami and tectum (arrows). d Using intermediate echo time, magnetic resonance spectroscopy detects an inverted doublet of lactate at 1.33 ppm.

Whole-exome sequencing identified a homozygous LRPPRC deletion, c.2726_2728del (p.Lys909del), classified as “likely pathogenic” and diagnostic of mitochondrial complex IV deficiency due to LRPPRC-related disease. Whole-exome sequencing was performed using the Twist Human Core Exome V2 kit (Twist Bioscience, South San Francisco, CA) on the Illumina NextSeq 2000 platform (Illumina, San Diego, CA, USA), generating paired-end 150 bp reads with an average coverage of ∼100×. Data were analyzed using the Genomize SEQ pipeline (Genomize Inc., Istanbul, Turkey), with alignment to the hg19 reference genome and variant calling by FreeBayes. Annotation and filtering were performed using multiple databases, including ClinVar, OMIM, and gnomAD. Sanger sequencing was performed for confirmation and segregation, which verified the homozygous variant in the patient and demonstrated heterozygosity in their parents. These findings consolidate the diagnosis of an early-onset, multisystem mitochondrial disorder driven by a rare LRPPRC variant, with cardinal manifestations of growth failure, neurodevelopmental impairment, metabolic acidosis, and cardiomyopathy.

Case 2

The proband’s 13-year-old sister, the first child of consanguineous Iraqi parents, exhibited global developmental delay, axial hypotonia, speech delay, and tremor beginning in early childhood. She first presented with hypotonia and an inability to ambulate at the age of three. Physical examination revealed significant growth retardation with a weight of 30 kg (SDS –3.45) and a height of 135 cm (SDS –3.84). Neurological examination demonstrated hyperreflexia in the lower extremities, dysmetria, postural tremor, and a broad-based, ataxic gait. There was no significant craniofacial dysmorphism; she only has arched eyebrows (Fig. 1b).

In the laboratory assessment, the complete blood count, renal and hepatic panels, creatine kinase, and serum electrolytes were unremarkable. A normal range of carnitine-acyl carnitine levels, plasma amino acid profiles, and urinary organic acid analysis was observed. Consequently, a brain MRI revealed no significant pathological findings.

Subsequent genetic testing via whole exome sequencing identified the same homozygous LRPPRC variant (c.2726_2728del; p.Lys909del) as detected in her younger sister, confirming the diagnosis of mitochondrial complex IV deficiency due to LRPPRC-related disease. This case further supports the phenotypic consistency observed among affected siblings, characterized by early-onset developmental delay, spasticity, ataxia, tremor and severe growth failure. These findings underscore the pathogenic significance of the LRPPRC c.2726_2728del variant and highlight its clinical relevance, particularly in populations with a high prevalence of consanguinity. The pedigree is illustrated in Figure 1c.

Discussion

The LRPPRC gene was first identified by Hou in 1994 and encodes a protein with 35 pentatricopeptide repeat (PPR) motifs [8]. The mutation underlying French-Canadian Leigh syndrome, which causes isolated COX deficiency in individuals from the Saguenay-Lac-Saint-Jean region of Quebec, was first described by Mootha et al. [7] in 2003. This mutation was mapped to chromosome 2 and was found to be associated with the disease phenotype. The founder effect, a term used to describe the process by which a new genetic variant becomes predominant within a population due to its recent introduction, has been observed in the Saguenay-Lac-Saint-Jean region of Quebec, Canada. This region has been found to have a significantly higher prevalence of a rare, autosomal recessive, monogenic mitochondrial disorder, with a carrier frequency of up to 1 in 23 adults and an incidence of 1 in 2,063 live births [9, 10]. In 2015, Oláhová et al. [11] demonstrated that LRPPRC mutations cause early-onset multisystemic mitochondrial disease in individuals from diverse ethnic backgrounds, including British, Pakistani, Indian, Turkish, and Iraqi populations. To date, to the best of our knowledge, 12 cases have been reported outside the Saguenay-Lac-Saint-Jean region. The present cases contribute to the expansion of the known phenotypic spectrum of French-Canadian Leigh syndrome.

LRPPRC mutations are biochemically characterized by an isolated complex IV deficiency, most prominent in skeletal muscle and liver. Patients typically present with persistently elevated lactate and pyruvate levels, reflecting impaired OXPHOS and increased reliance on anaerobic metabolism. Functional studies have demonstrated reduced levels of LRPPRC protein, defective assembly and enzymatic activity of complex IV, and decreased steady-state expression of multiple OXPHOS subunits. In some tissues, secondary complex I abnormalities have also been observed, indicating a broader impact on respiratory chain integrity. These findings underscore the dual biochemical and functional role of LRPPRC in stabilizing mitochondrial transcripts and ensuring proper OXPHOS, thereby accounting for the metabolic and clinical manifestations associated with LRPPRC deficiency. The findings of Oláhová et al. [11] cohort demonstrated consistency across 10 patients from 7 families. The most frequently observed features include global developmental delay, hypotonia, recurrent episodes of lactic acidosis, and feeding difficulties leading to failure to thrive. Motor regression is a frequently reported phenomenon and is often precipitated by infections. The patient’s symptoms also include ataxia, dysphagia, spasticity, postural tremor, epileptic seizures, delayed speech, and dysarthria. In certain instances, the condition can also result in cardiomyopathy and respiratory failure. Some patients may present with arterial hypertension and abnormal ocular movements, including esotropia and nystagmus. The following characteristics are commonly associated with dysmorphic craniofacial features: prominent foreheads, hypertelorism, anteverted nares, arched eyebrows, and midfacial hypoplasia [9, 12]. Case 1 is characterized by a prominent forehead and arched eyebrows, while Case 2 also exhibits arched eyebrows.

Laboratory evaluations frequently yield the presence of isolated COX deficiency, elevated serum lactate levels, and abnormal organic acid profiles [11, 12]. In the majority of previously documented cases, liver and kidney function tests, complete blood counts, plasma amino acid analyses, plasma carnitine/acylcarnitine profiles, and urinary organic acid analyses were found to be within normal limits. However, severe lactic acidosis, hyperammonemia, hypoglycemia, ketonemia, and ketonuria have also been documented. A limited number of patients exhibited elevated alanine levels in plasma amino acid analyses and increased tricarboxylic acid cycle intermediates in urinary organic acid analyses. A hallmark of biochemical consistency was identified in nearly all cases, characterized by the presence of persistent or intermittent lactic acidosis [11–13]. In both cases, persistent lactic acidosis exacerbated by infections was a prominent and shared feature, consistent with previously published cases. In Case 1, urinary organic acid analysis revealed elevated levels of 4-hydroxypyruvic acid. Liver and renal function tests were within the normal range in both cases, consistent with the majority of reported LRPPRC cases.

The extant literature on cardiac findings includes congenital heart defects, such as a bicuspid aortic valve and HCM, as detected by echocardiography [11]. Case 1 exhibited HCM as indicated by echocardiography, a finding that aligns with existing literature on the subject. However, the echocardiographic findings of Case 2 were unremarkable.

A multitude of cranial MRI abnormalities have been documented in patients with LRPPRC gene mutations, as outlined in the extant literature. These neuroimaging findings support the clinical diagnosis and are most consistent with symmetric signal hyperintensities in the brainstem and basal ganglia, which are characteristic of Leigh syndrome. Other common findings include cerebellar atrophy, abnormal cerebellar signals, and cerebral structural anomalies, such as polymicrogyria or agenesis of the corpus callosum. Furthermore, the presence of symmetric leukoencephalopathy with restricted diffusion in the periventricular or subcortical white matter may be detected. MRI findings may include Leigh-like changes, which manifest as signal abnormalities in the brainstem and basal ganglia [11]. In accordance with prior reports, Case 1’s cranial MRI exhibited symmetrical hyperintense signal alterations on T2-weighted and FLAIR sequences within the tectal region of the mesencephalon and medial thalami. Central cavitation-like areas and cerebellar atrophy manifested. The patient did not demonstrate any anomalies in cerebral structure or restricted diffusion as indicated by diffusion tensor imaging. An inverted lactate peak was demonstrated at the thalamic level. No atypical MRI findings were identified in the second patient.

To date, a total of 343 pathogenic variants have been reported in the LRPPRC gene. Of the aforementioned mutations, 327 are classified as loss-of-function mutations, 10 are designated as missense mutations, and six are categorized as non-coding mutations (Franklin–Genoox Clinical Database, 2025). A clear genotype-phenotype correlation among the reported LRPPRC variants is not evident. The most common variant in the French-Canadian population is c.1061C>T [1]. Outside of the Saguenay-Lac-Saint-Jean region, the most prevalent variant is 3900 + 1G>T. A variety of mutations have been identified in diverse populations. One such example is c.2726_2728delAGA (p.Lys909del), which was previously reported in only one Iraqi patient [11]. This female patient, born to first-cousin Iraqi parents, presented with developmental delay, hypotonia, truncal ataxia, and dysmetria by 6 months of age. During periods of viral infection, her symptoms intensified, resulting in a loss of motor skills that precluded her from independent ambulation, requiring assistance. At 23 months of age, the patient exhibited esotropia, marked motor regression, dysphagia, hypertension, and left ventricular hypertrophy. PEG placement and subsequent tracheostomy were necessitated by the progressive deterioration of the patient’s respiratory function. By the age of 27 months, she was receiving palliative care in the comfort of her own home. The subject’s MRI findings exhibited symmetrical signal abnormalities involving the corpus callosum, spinocerebellar tracts, and inferior olivary nuclei. These abnormalities demonstrated restricted diffusion [11]. The cases presented herein constitute the second and third documented cases in the extant literature with this particular mutation, thereby underscoring its clinical significance. The initial patient presented with developmental delay, motor regression, hypotonia, ataxia, and dysmetria. The patient’s motor functions and laboratory findings, including elevated lactate levels, exhibited deterioration during the course of viral infections. Additionally, the subject has been diagnosed with cardiomyopathy. A significant increase in lactate and 4-hydroxypyruvic acid levels was observed. Her MRI findings were consistent with these descriptions, thereby further supporting the diagnosis. When comparing the previously reported Iraqi patient with our first case, several shared clinical characteristics become evident. Both patients were born to consanguineous parents and exhibited early-onset neurodevelopmental delay, hypotonia, and progressive neurological deterioration, with episodes of acute decompensation triggered by infections. Importantly, both patients also demonstrated symmetrical signal abnormalities on MRI and left ventricular hypertrophy. However, our patient additionally showed cerebellar involvement and other ophthalmologic manifestations, underscoring the phenotypic variability even among patients of similar ethnic background carrying LRPPRC mutations. This comparison highlights both the overlapping core features and the broad clinical heterogeneity associated with LRPPRC deficiency. The recurrence of the same LRPPRC variant (c.2726_2728del) in unrelated Iraqi patients suggests a possible founder effect. Similar phenomena have been reported in Middle Eastern populations, including Iraqis, for genes such as MEFV in familial Mediterranean fever [14] and GJB2 in hereditary hearing loss, where specific variants reach high frequencies due to historical founder events combined with consanguinity [15]. Thus, the clustering of this LRPPRC variant in Iraqi families may also reflect a population-specific founder effect. We also suggest that future studies may investigate the carrier frequency of this variant in Iraqi populations to further support the possible founder effect.

Ambiguous genitalia was observed in the first patient, as previously described in a single case in the literature [16]; however, attributing this finding solely to the LRPPRC mutation is difficult, as the patient was also diagnosed with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, confirmed biochemically and genetically, representing an independent condition unrelated to the primary mutation. Additional case reports are needed to establish a clear association between LRPPRC mutations and the occurrence of ambiguous genitalia. As with previously documented cases, the second patient exhibited global developmental delay, hypotonia, ataxia, dysmetria, and tremor. The patient’s metabolic findings were nonspecific, and she exhibited persistent hyperlactatemia. Notably, neuroimaging and echocardiographic evaluations revealed no significant findings.

The occurrence of mutations in the LRPPRC gene has been identified as a rare cause of metabolic encephalopathy in the Quebec population. Prior to this, only a limited number of cases had been documented outside of Quebec. For instance, an Italian male subject was found to carry a compound heterozygous mutation in the LRPPRC gene, specifically characterized by the presence of c.1921–7A>G and c.2056A>G, resulting in a p.Ile686Val alteration [12]. Another case, involving a Chinese male, exhibited novel compound heterozygous missense mutations in the LRPPRC gene, marked by c.3130C>T, c.3430C>T, and c.4078G>A variations [13]. A female subject from the Middle East has been identified as homozygous for the c.515A>G mutation. The (Tyr172Cys) missense variant has been identified in the LRPPRC gene [17].

The present case series is among the few examples from outside the Saguenay-Lac-Saint-Jean region, and to the best of our knowledge, it is also the second and third such case observed in Turkey. We emphasize that our report represents the second and third Iraqi siblings with the same LRPPRC mutation, highlighting striking intrafamilial variability and expanding the known phenotypic spectrum. The similarities and differences between the 2 patients are summarized in Table 1. The most remarkable difference is that the younger sibling had HCM and MRI abnormalities, while the older sibling presented a milder phenotype without cardiac or neuroimaging findings.

Table 1.

Comparison of clinical features of the two siblings with LRPPRC mutation

Clinical features	Case 1	Case 2
Age/sex	9 years, female	13 years, female
Growth	Severe growth failure (weight SDS –3.5; height SDS –4.37)	Severe growth failure (weight SDS –3.45; height SDS –3.84)
Developmental delay	Global developmental delay	Global developmental delay
Neurological findings	Hypotonia, spastic ataxic gait, tremor, dysmetria, hyperreflexia, titubation	Axial hypotonia, tremor, dysmetria, ataxia, hyperreflexia
Other clinical features	Ambiguous genitalia (Prader 5), café-au-lait macules, arched eyebrows, prominent forehead	Arched eyebrows, no major dysmorphic features
Laboratory findings	Serum lactate ↑, pyruvate ↑, urine organic acids: 4-hydroxypyruvic acid ↑	Persistent hyperlactatemia; otherwise normal metabolic panel
Neuroimaging	Symmetrical mesencephalon, thalami hyperintensities, cerebellar atrophy, inverted lactate peak on MRS	No significant MRI abnormalities
Cardiac	HCM (LVMI 49 g/m2.7)	Normal echocardiography
Genetics	Homozygous LRPPRC c.2726_2728del (p.Lys909del)	Same homozygous LRPPRC c.2726_2728del (p.Lys909del)

LVMI, left ventricular mass index.

To delineate the full spectrum of clinical and biochemical manifestations associated with this mutation, additional case reports are required. By presenting these two siblings, we contribute to the characterization of a rare LRPPRC variant, thereby expanding the current knowledge on its phenotypic spectrum and clinical relevance.

Conclusion

Mitochondrial disease due to LRPPRC mutations should be considered in patients presenting with early-onset neurodevelopmental delay, hypotonia, ataxia, tremor, spasticity, MRI findings suggestive of Leigh syndrome, and persistent hyperlactatemia, particularly in consanguineous populations. Whole exome sequencing should be considered a diagnostic tool in patients presenting with comparable symptoms, even when routine metabolic tests are unremarkable. The reporting of additional cases will contribute to a better understanding of genotype-phenotype correlations and expand the known mutational spectrum associated with this rare disorder.

Acknowledgments

The authors would like to thank the patients and the families for allowing the publication of their cases.

Statement of Ethics

Ethics approval was not required because it is a retrospective case report. The Ankara University Ethics Committee made that decision. Ethical approval was not required for this study in accordance with local/national guidelines. Written informed consent was obtained from the parent/legal guardian of the patient for publication of the details of their medical case and any accompanying images. The CARE Checklist has been completed by the authors for this case report and is attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000548731).

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The authors received no financial support for the research, authorship, and/or publication of this article.

Author Contributions

Study design and visualization: Merve Setenay Akyüzlüer Güneş and Engin Köse. Clinical data: Merve Setenay Akyüzlüer Güneş, Miraç Yıldırım, Ömer Erdeve, and Emine Kübra Şen. Molecular experiments and data analysis: Duygu Duman and Fatma Tuba Eminoğlu. Manuscript preparation: Merve Setenay Akyüzlüer Güneş, Engin Köse, and Elif Özsu.

Funding Statement

The authors received no financial support for the research, authorship, and/or publication of this article.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.