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].
Table 2.
Common Clinical Manifestations of SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria
View in own window
Frequency | Manifestations |
---|
>75%
|
|
50%-75%
|
|
25%-50%
|
|
<25%
| Choreoathetosis Distinctive facial features incl brachycephaly, epicanthus, upslanted palpebral fissures Epilepsy Gastroesophageal reflux disease Hyperhidrosis Hypertonia Hypoglycemia Joint contractures Kyphoscoliosis Ophthalmoplegia Ptosis Strabismus Recurrent respiratory infections Recurrent vomiting Respiratory distress
|
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:
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].
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].