SUCLG1-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria

Clinical characteristics.

SUCLG1-related mitochondrial DNA (mtDNA) depletion syndrome, encephalomyopathic form with methylmalonic aciduria is characterized in the majority of affected newborns by hypotonia, muscle atrophy, feeding difficulties, and lactic acidosis. Affected infants commonly manifest developmental delay / cognitive impairment, growth retardation / failure to thrive, hepatopathy, sensorineural hearing impairment, dystonia, and hypertonia. Notable findings in some affected individuals include hypertrophic cardiomyopathy, epilepsy, myoclonus, microcephaly, sleep disturbance, rhabdomyolysis, contractures, hypothermia, and/or hypoglycemia. Life span is shortened, with median survival of 20 months.

Diagnosis/testing.

The diagnosis of SUCLG1-related mtDNA depletion syndrome is established in a proband by the identification of biallelic pathogenic variants in SUCLG1 on molecular genetic testing.

Management.

Treatment of manifestations: Management is supportive and is best provided by a multidisciplinary team. Treatment may include physical therapy to help maintain muscle function and prevent joint contractures, nutritional support by a dietitian, use of a nasogastric tube or gastrostomy tube feedings, chest physiotherapy, and aggressive antibiotic treatment of chest infections. When present, seizures are treated using standard anti-seizure medication.

Surveillance: The suggested evaluations (with frequency varying according to the needs of the child) can include developmental and neurologic assessment, nutritional and growth assessment, echocardiogram, liver function tests, hearing evaluation, and ophthalmologic examination.

Genetic counseling.

SUCLG1-related mtDNA depletion syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SUCLG1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

SUCLG1-related mitochondrial DNA (mtDNA) depletion syndrome, encephalomyopathic form with methylmalonic aciduria (MMA) typically manifests at birth or during early infancy and should be suspected in individuals with a combination of the following supportive clinical, brain MRI, laboratory, and muscle biopsy findings.

Clinical features

Present in >50%:

• Developmental delay and cognitive impairment
• Hypotonia
• Muscle atrophy
• Feeding difficulties

Present in 20%-50%:

• Growth retardation / failure to thrive
• Hepatopathy
• Sensorineural hearing impairment
• Dystonia
• Hypertonia

Present in <20%:

• Hypertrophic cardiomyopathy
• Recurrent respiratory infections, respiratory distress, and apnea
• Recurrent vomiting and gastroesophageal reflux disease
• Ptosis and strabismus
• Epilepsy, myoclonus, and microcephaly
• Hyperhidrosis
• Sleep disturbance
• Rhabdomyolysis
• Contractures
• Hypothermia

Brain MRI findings [Carrozzo et al 2016]

• Basal ganglia hyperintensities (80%)
• Cerebral atrophy (30%)
• Leukoencephalopathy (20%)

Supportive laboratory findings

• Urine organic acid analysis
  • Elevation of urinary methylmalonic acid (MMA) in all affected children. Urinary MMA ranges from 10 to 500 mmol/mol creatinine (normal <3 mmol/mol creatinine).
    Note: In classic methylmalonic aciduria urinary MMA is ~1,000-10,000 mmol/mol creatinine, and in defects of cobalamin metabolism urinary MMA is ~100s mmol/mol creatinine (see Differential Diagnosis).
  • Several other metabolites that may be elevated in urine include methylcitrate, 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and Krebs cycle intermediates (e.g., succinate, fumarate, 2-ketoglutarate).
• Plasma MMA level is elevated in all affected children and ranges from 1 to10 mmol/L (normal <0.3 mmol/L). Note: In classic methylmalonic aciduria plasma MMA is ~100-1,000 mmol/L, and in defects of cobalamin metabolism plasma MMA is ~10s mmol/L (see Differential Diagnosis).
• Acylcarnitine profile can show elevated C3; thus, this condition can potentially be detected by newborn screening.
• Plasma and CSF lactate levels are elevated in most affected individuals.
• Hypoglycemia can occasionally occur [Carrozzo et al 2016].

Muscle biopsy, typically performed during the evaluation of individuals with mitochondrial diseases, can show variable abnormalities or can occasionally be normal. The following findings can suggest the diagnosis:

• Increased fiber size variability, atrophic fibers, intracellular lipid accumulation, ragged-red fibers (RRF), and COX-deficient fibers
• Structurally altered mitochondria with abnormal cristae on electron microscopy
• Abnormal electron transport chain activity. The most common abnormalities are combined complex I and IV deficiencies, combined complex I, III, and IV deficiencies, and isolated complex IV deficiency.
• Reduced mtDNA content; typically 15%-50% of tissue- and age-matched controls [Ostergaard et al 2007, Valayannopoulos et al 2010, Randolph et al 2011, Landsverk et al 2014]

Establishing the Diagnosis

The diagnosis of SUCLG1-related mtDNA depletion syndrome is established in a proband by the identification of biallelic pathogenic (or likely pathogenic) variants in SUCLG1 on molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) Identification of biallelic SUCLG1 variants of uncertain significance (or of one known SUCLG1 pathogenic variant and one SUCLG1 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and genomic testing (comprehensive genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of SUCLG1-related mtDNA depletion syndrome is broad, children with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from other inherited mitochondrial disorders are more likely to be diagnosed using genomic testing (see Option 2).

Option 2

When the phenotype is indistinguishable from many other inherited mitochondrial disorders, molecular genetic testing approaches can include genomic testing (comprehensive genome sequencing) and/or gene-targeted testing (multigene panel):

• Comprehensive genome sequencing (when clinically available) includes exome sequencing and genome sequencing.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
• A multigene panel for inherited mitochondrial disorders may also be considered.

Table 1.

Molecular Genetic Testing Used in SUCLG1-Related mtDNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria

Clinical Description

To date 29 individuals with SUCLG1-related mitochondrial DNA (mtDNA) depletion syndrome, encephalomyopathic form with methylmalonic aciduria (MMA) have been reported [Ostergaard et al 2007, Ostergaard et al 2010, Rivera et al 2010, Rouzier et al 2010, Valayannopoulos et al 2010, Van Hove et al 2010, Randolph et al 2011, Sakamoto et al 2011, Honzik et al 2012, Navarro-Sastre et al 2012, Landsverk et al 2014, Carrozzo et al 2016, Chu et al 2016, Donti et al 2016, Liu et al 2016, Pupavac et al 2016].

The clinical description here is based on the findings reported in these 29 individuals. The common clinical manifestations are summarized in Table 2 [Carrozzo et al 2016].

Table 2.

Clinical Manifestations of SUCLG1-Related mtDNA Depletion Syndrome

Age of onset and phenotypic spectrum. Although SUCLG1-related mtDNA depletion syndrome can present from the prenatal period to age one year, the majority of affected infants present at birth [Carrozzo et al 2016].

The majority have an uncomplicated pregnancy and normal birth weight; however, five neonates had intrauterine growth restriction (IUGR) or were small for gestational age (SGA) [Ostergaard et al 2007, Randolph et al 2011, Carrozzo et al 2016]. Rare prenatal manifestations may include oligohydramnios and abnormal fetal heart rate [Carrozzo et al 2016].

The majority of affected infants present with early-onset encephalomyopathy and neurocognitive problems as well as hepatopathy, feeding and growth problems, and cardiorespiratory complications.

Death from severe metabolic acidosis during the neonatal period (fatal infantile lactic acidosis) has been reported in five infants [Ostergaard et al 2007, Rivera et al 2010].

Neurocognitive. The majority of affected children demonstrate developmental delay, cognitive impairment, hypotonia, and muscle atrophy. Other, less frequent, neurologic manifestations include: sensorineural hearing impairment, dystonia, hypertonia, epilepsy, myoclonus, microcephaly, choreoathetosis, ptosis, and strabismus.

Hepatopathy. Approximately 40% of affected individuals have liver involvement manifesting as hepatomegaly, steatosis, and elevated liver enzymes. One affected infant developed intermittent episodes of liver failure [Van Hove et al 2010].

Feeding and growth. Failure to thrive, growth retardation, and feeding difficulties, often necessitating tube feeding, occur commonly. Recurrent vomiting and gastroesophageal reflux disease (GERD) occasionally occur. The feeding difficulties, recurrent vomiting, and GERD can cause or contribute to growth failure.

Cardiac. Hypertrophic cardiomyopathy was reported in 15% of affected children. Ventricular hypertrophy is typically mild and appears in the neonatal period or infancy [Carrozzo et al 2016].

Respiratory. Recurrent respiratory infections are reported in some. Respiratory distress due to muscle weakness, apnea, and abnormal breathing has been reported.

Congenital malformations. One affected infant had multiple congenital anomalies including cleft lip and palate, aortic coarctation, patent ductus arteriosus, patent foramen ovale, shortening of the left femur and both humeri, dilatation of the left renal collecting system, and accessory left kidney [Landsverk et al 2014].

Other congenital anomalies reported in single infants each are interrupted aortic arch, polydactyly, and hypospadias [Ostergaard et al 2007, Rivera et al 2010].

Metabolic derangements. In addition to elevated MMA, the majority of affected children develop lactic acidosis that can be severe and life threatening. Hypoglycemia was occasionally reported.

Others. Other, less frequent, manifestations include hyperhidrosis, hypothermia, sleeping disturbance, rhabdomyolysis, and joint contractures.

Prognosis. Life span is shortened, with median survival of 20 months. Two thirds (14/21) of affected children died during childhood – five in the neonatal period and nine during infancy and early childhood [Carrozzo et al 2016].

Genotype-Phenotype Correlations

Pathogenic SUCLG1 missense variants can result in some residual enzyme activity, and hence a milder phenotype. Survival in children with biallelic pathogenic missense variants was longer (median age: 18 months) than in children with biallelic loss-of-function variants (splice site, frameshift, and nonsense variants) (median age: birth) [Carrozzo et al 2016].

Nomenclature

Succinyl-CoA ligase deficiency can result from either biallelic pathogenic variants in SUCLG1 (SUCLG1-related mtDNA depletion syndrome) or biallelic pathogenic variants in SUCLA2 (SUCLA2-related mtDNA depletion syndrome).

Prevalence

SUCLG1-related mtDNA depletion syndrome is rare; the exact prevalence is unknown. To date 29 individuals with SUCLG1-related mtDNA depletion have been reported in families of different ethnic origins [Ostergaard et al 2007, Ostergaard et al 2010, Rivera et al 2010, Rouzier et al 2010, Valayannopoulos et al 2010, Van Hove et al 2010, Randolph et al 2011, Sakamoto et al 2011, Honzik et al 2012, Navarro-Sastre et al 2012, Landsverk et al 2014, Carrozzo et al 2016, Chu et al 2016, Donti et al 2016, Liu et al 2016, Pupavac et al 2016].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SUCLG1-related mtDNA depletion syndrome the following evaluations are recommended:

• Comprehensive neurologic examination and developmental/cognitive assessment. The following diagnostic modalities can be considered to assess the degree of neurologic involvement:
  • Brain MRI (if not performed during the diagnostic evaluation) to establish the degree of central nervous system involvement
  • EEG if seizures are suspected
• Echocardiogram to assess for cardiomyopathy
• Liver function tests including transaminases, albumin, total and direct bilirubin, and coagulation profile
• Audiologic evaluation
• Ophthalmologic examination for evidence of ptosis and/or strabismus
• Nutritional evaluation and swallowing assessment for feeding difficulties and growth failure
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Management is best provided by a multidisciplinary team including specialists in neurology, audiology, child development, gastroenterology, cardiology, nutrition, and clinical genetics. Treatments include the following:

• Physical therapy to help maintain muscle function and prevent joint contractures
• Standard treatment with anti-seizure medication for seizures
• Nutritional support by a dietitian and the use of a nasogastric tube or gastrostomy tube feedings to address feeding difficulties and failure to thrive
• Chest physiotherapy, aggressive antibiotic treatment of chest infections, and artificial ventilation (including assisted nasal ventilation or intubation and the use of a tracheostomy and ventilator) for respiratory insufficiency
• Hypertrophic cardiomyopathy and hepatopathy, when present, require standard management by cardiologists and hepatologists, respectively.

Surveillance

No clinical guidelines for surveillance are available.

The following evaluations are suggested, with frequency varying according to the needs of the child:

• Developmental and neurologic assessment
• Nutritional and growth assessment
• Echocardiogram
• Liver function tests
• Hearing evaluation
• Ophthalmologic examination

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

A group of mtDNA depletion syndromes is caused by defects in genes encoding proteins involved in maintenance of the mitochondrial deoxyribonucleotide pool. Because in vitro experimental studies have demonstrated improved mtDNA content following deoxyribonucleotide supplementation, this could potentially be a treatment for some mtDNA depletion syndromes [Cámara et al 2014].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

SUCLG1-related mitochondrial DNA (mtDNA) depletion syndrome, encephalomyopathic form with methylmalonic aciduria is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one SUCLG1 pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Individuals with SUCLG1-related mtDNA depletion syndrome are not reported to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a SUCLG1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SUCLG1 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the SUCLG1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Molecular Pathogenesis

Succinyl-CoA ligase (SUCL) is a mitochondrial heterodimeric enzyme of the Krebs cycle that is composed of an alpha subunit, encoded by SUCLG1, and a beta subunit, encoded by either SUCLA2 or SUCLG2. SUCL catalyzes the reversible conversion of succinyl-CoA and ADP or GDP to succinate and ATP or GTP. When the alpha subunit forms a heterodimer with SUCLA2-encoded beta subunits, the resulting SUCL enzyme utilizes ADP to generate ATP. In contrast, when the alpha subunit forms a heterodimer with SUCLG2-encoded beta subunits, the resulting SUCL enzyme utilizes GDP to generate GTP.

SUCL also forms a complex with the mitochondrial nucleoside diphosphate kinase (see Abnormal gene product).

Gene structure. SUCLG1 contains nine exons (NM_003849.3).

Pathogenic variants. The spectrum of reported SUCLG1 pathogenic variants includes missense, splice site, frameshift deletion, and nonsense variants. Missense variants are the most common, accounting for about half of pathogenic variants.

Normal gene product. SUCLG1 encodes the succinyl-CoA ligase [ADP/GDP-forming] subunit alpha of SUCL, which has 346 amino acid residues (NP_003840.2).

Abnormal gene product. Pathogenic SUCLG1 variants lead to dysfunctional SUCL protein. As SUCL forms a complex with the mitochondrial nucleoside diphosphate kinase, the lack of this complex in SUCL deficiency can disturb the kinase function, resulting in decreased mitochondrial nucleotide synthesis and, therefore, decreased mtDNA synthesis leading to mtDNA depletion. In addition, because SUCL deficiency results in impaired conversion of succinyl-CoA to succinate, succinyl-CoA accumulates and is converted to methylmalonyl-CoA by methylmalonyl-CoA mutase, leading to the accumulation of methylmalonic acid (MMA) [El-Hattab & Scaglia 2013].

Revision History

• 30 March 2017 (bp) Review posted live
• 20 October 2016 (aeh) Original submission

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