Sucla2-Related Mitochondrial Dna Depletion Syndrome, Encephalomyopathic Form With Methylmalonic Aciduria

Clinical characteristics.

SUCLA2-related mitochondrial DNA (mtDNA) depletion syndrome, encephalomyopathic form with methylmalonic aciduria is characterized by onset of the following features in infancy or childhood (median age of onset 2 months; range of onset birth to 6 years): psychomotor retardation, hypotonia, dystonia, muscular atrophy, sensorineural hearing impairment, postnatal growth retardation, and feeding difficulties. Other, less frequent, features include distinctive facial features, contractures, kyphoscoliosis, gastroesophageal reflux, ptosis, choreoathetosis, ophthalmoplegia, and epilepsy (infantile spasms or generalized convulsions). The median survival is 20 years; approximately 30% of affected individuals succumb during childhood. Affected individuals may have hyperintensities in the basal ganglia, cerebral atrophy, and leukoencephalopathy on head MRI. Elevation of methylmalonic acid (MMA) in the urine and plasma is found in a vast majority of affected individuals, although at levels that are far below those typically seen in individuals with classic methylmalonic aciduria.

Diagnosis/testing.

The diagnosis of SUCLA2-related mtDNA depletion syndrome is established in a proband by the identification of biallelic pathogenic variants in SUCLA2 on molecular genetic testing.

Management.

Treatment of manifestations: Physical therapy to maintain muscle function and prevent joint contractures; antiepileptic drugs for seizures; nasogastric or gastrostomy tube as needed to assure adequate caloric intake; chest physiotherapy, aggressive antibiotic treatment of chest infections, and respiratory aids such as assisted nasal ventilation or use of a tracheostomy and ventilator when indicated; bracing to treat scoliosis or kyphosis; blepharoplasty for significant ptosis; and hearing aids/cochlear implantation for sensorineural hearing loss.

Surveillance: Routine monitoring of development, growth, and hearing; periodic ophthalmologic evaluations; routine skeletal evaluations for kyphoscoliosis and joint contractures.

Genetic counseling.

SUCLA2-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. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible once the pathogenic variants in the family have been identified.

Suggestive Findings

SUCLA2-related mitochondrial DNA (mtDNA) depletion syndrome, encephalomyopathic form with methylmalonic aciduria typically manifests during early infancy and should be suspected in individuals with a combination of the following clinical, brain MRI, and supportive laboratory and muscle biopsy findings.

Clinical features

• Psychomotor retardation
• Hypotonia
• Sensorineural hearing impairment
• Dystonia
• Feeding difficulties
• Growth retardation / failure to thrive
• Muscular atrophy

Brain MRI findings

• Basal ganglia hyperintensities
• Cerebral atrophy
• Leukoencephalopathy

Supportive laboratory findings

• Urine organic acid analysis
  • Elevation of methylmalonic acid (MMA) in the vast majority of affected children. However, the MMA level is considerably less pronounced than in classic methylmalonic aciduria and can be only marginally elevated or even normal on rare occasions [Lamperti et al 2012].
  • Several other metabolites may be elevated in urine, including methylcitrate, 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and Krebs cycle intermediates such as succinate, fumarate, and 2-ketoglutarate [Carrozzo et al 2016].
• Plasma MMA level
  • Elevation has been reported in all affected individuals analyzed, including those with marginally elevated urine MMA level [Carrozzo et al 2016].
  • Plasma MMA level may be more sensitive in identifying SUCLA2-related mtDNA depletion syndrome than urine organic acid analysis.
• Acylcarnitine profile. Elevated C3; thus, this condition can potentially be detected by newborn screening.
• Plasma and CSF lactate levels. Elevated in most affected individuals

Muscle biopsy findings

• Increased fiber size variability, atrophic fibers, intracellular lipid accumulation, and COX-deficient fibers
  Approximately 20% of affected individuals will have normal muscle histology [Carrozzo et al 2016].
• In some cases, structurally altered mitochondria with abnormal cristae on electron microscopy
• In the majority of individuals, 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.
  • Electron transport chain activity has been reported to be normal in approximately 10% of affected individuals who underwent this test [Carrozzo et al 2016].
• Mitochondrial DNA content in muscle tissue of affected individuals typically reduced to 20%-60% of tissue- and age-matched controls [Elpeleg et al 2005, Carrozzo et al 2007, Ostergaard et al 2007, Carrozzo et al 2016]

Establishing the Diagnosis

The diagnosis of SUCLA2-related mtDNA depletion syndrome is established in a proband by the identification of biallelic pathogenic variants in SUCLA2 on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Sequence analysis of SUCLA2 is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
  Note: Targeted analysis for the c.534+1G>A pathogenic founder variant can be performed first in individuals of Faroese ancestry (see Prevalence).
• A multigene panel that includes SUCLA2 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes SUCLA2) fails to confirm a diagnosis in an individual with features of SUCLA2-related mtDNA depletion syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

To date 50 individuals with SUCLA2-related mtDNA depletion syndrome have been reported [Elpeleg et al 2005, Carrozzo et al 2007, Ostergaard et al 2007, Morava et al 2009, Lamperti et al 2012, Navarro-Sastre et al 2012, Jaberi et al 2013, Matilainen et al 2015, Nogueira et al 2015, Carrozzo et al 2016]. The clinical description here is based on what has been reported in these 50 individuals. The common clinical manifestations are summarized in Table 2 [Carrozzo et al 2016].

Affected children with SUCLA2-related mtDNA depletion syndrome typically have an uncomplicated prenatal course and birth. Birth weight and birth length are typically within the normal range. The median age of onset of manifestations is two months, with a range from birth to six years [Carrozzo et al 2016].

Neurocognitive. The vast majority of affected children present during infancy with hypotonia and psychomotor retardation. Dystonia and muscle atrophy also occur commonly. Other, less frequent, neurologic manifestations include hypertonia, choreoathetosis, ptosis, ophthalmoplegia, strabismus, and epilepsy (including infantile spasms and generalized convulsions). Brain MRI typically shows basal ganglia hyperintensities (70%), cerebral atrophy (70%), and leukoencephalopathy (15%) [Carrozzo et al 2016].

Hearing. Most affected children develop sensorineural hearing impairment; some benefit from a cochlear implant.

Growth. Postnatal growth retardation with low weight and length/height is a common feature of this condition. Feeding difficulties, often necessitating tube feeding, occur commonly, while recurrent vomiting and gastroesophageal reflux disease occasionally occur. The feeding difficulties, recurrent vomiting, and gastroesophageal reflux disease can lead or contribute to failure to thrive in affected infants.

Distinctive facial features including brachycephaly, epicanthus, and upslanted palpebral fissures, have been reported.

Respiratory. Recurrent respiratory infections occur occasionally. Respiratory distress due to muscle weakness, obstructive sleep apnea, tracheomalacia, and abnormal breathing has also been reported.

Skeletal. Progressive kyphoscoliosis has been reported occasionally and may require treatment. Joint contractures can develop in extremities secondary to decreased movement.

Other. Hyperhidrosis and neonatal hypoglycemia have occasionally been reported. Other rare manifestations:

• Anemia
• Acquired dislocation of hip and shoulder
• Irritability
• Sleep disturbance

Life span is shortened, with median survival of 20 years in individuals with SUCLA2-related mtDNA depletion syndrome. Approximately 30% of affected individuals reportedly died during childhood [Carrozzo et al 2016].

Genotype-Phenotype Correlations

Pathogenic missense variants can result in some residual enzyme activity, and hence a milder phenotype. Survival in affected individuals with biallelic pathogenic missense variants was significantly longer than in those with biallelic loss-of-function variants (deletions, frameshift and nonsense variants) (median survival age 21 years vs 15 years) [Carrozzo et al 2016].

Prevalence

SUCLA2-related mtDNA depletion syndrome is rare; the exact prevalence is unknown. To date, 50 individuals of different ethnic origins have been reported [Elpeleg et al 2005, Carrozzo et al 2007, Ostergaard et al 2007, Morava et al 2009, Lamperti et al 2012, Navarro-Sastre et al 2012, Jaberi et al 2013, Matilainen et al 2015, Nogueira et al 2015, Carrozzo et al 2016].

A founder pathogenic variant in families of Faroese origin has been identified (Table 4); the disorder has a high incidence (1:1,700) and a carrier frequency of 1:33 in the Faroe Islands [Ostergaard et al 2007].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SUCLA2-related mtDNA depletion syndrome, the following evaluations need to be performed (if not already done as part of the initial diagnostic evaluation):

• Comprehensive neurologic examination and developmental/cognitive assessment. The following diagnostic modalities can be used to assess the degree of neurologic involvement:
  • Neuroimaging (preferably brain MRI) to establish the degree of central nervous system involvement
  • EMG to assess myopathy
  • EEG if seizures are suspected
• Audiologic evaluation
• Ophthalmologic examination
• Nutritional evaluation and swallowing assessment for feeding difficulties and growth failure
• Physical examination for the back and joints for kyphoscoliosis and joint contractures
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Management should involve a multidisciplinary team including specialists in neurology, audiology, child development, gastroenterology, nutrition, and clinical genetics. Treatments include the following:

• Physical therapy to help maintain muscle function and prevent joint contractures
• Standard treatment with antiepileptic drugs 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
• Bracing for scoliosis and kyphosis
• Blepharoplasty for significant ptosis
• Hearing aids and/or cochlear implantation for sensorineural hearing loss

Surveillance

No clinical guidelines for surveillance are available. The following evaluations are suggested, with frequency varying according to the severity of the condition:

• Routine developmental and neurologic assessment
• Periodic nutritional and growth assessment
• Periodic hearing evaluation
• Periodic ophthalmologic examination
• Routine physical examination of back and joints for kyphoscoliosis and joint contractures

Evaluation of Relatives at Risk

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

Therapies Under Investigation

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. Note: There may not be clinical trials for this disorder.