Diagnostic Criteria

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%:

Source: GeneReviews — "SUCLG1-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria"

Differential Diagnosis

SUCLG1-related mtDNA depletion syndrome needs to be differentiated from other mtDNA depletion syndromes, a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. includes the currently known mtDNA depletion syndromes. Mitochondrial DNA depletion syndromes occur as a result of defects in mtDNA maintenance caused by pathogenic variants in nuclear genes that function in either mitochondrial nucleotide synthesis (e.g., TK2, SUCLA2, SUCLG1, RRM2B, DGUOK, and TYMP) or mtDNA replication (e.g., POLG and TWNK [C10orf2]). The function of FBXL4 is not yet known. Mitochondrial DNA depletion syndromes are phenotypically classified into hepatocerebral, encephalomyopathic, neurogastrointestinal, and myopathic forms . Table 3. Mitochondrial DNA Depletion Syndromes

Management Guidelines

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:

Source: GeneReviews — "SUCLG1-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria"

Surveillance Guidelines

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

Source: GeneReviews — "SUCLG1-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria"