Clinical Description
FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals to date [Bonnen et al 2013, Gai et al 2013, Huemer et al 2015, Antoun et al 2016, Barøy et al 2016, Pronicka et al 2016, van Rij et al 2016, Dai et al 2017, Morton et al 2017]. It mainly presents as congenital lactic acidosis along with developmental delay, other neurologic manifestations, feeding difficulty, growth failure, and variable involvement of other organs.
Age of onset was soon after birth in the majority of reported individuals (median age of onset: one day; range 1 day – 13 years). Only five individuals presented after age six months, including a female presenting at age 13 years [Pronicka et al 2016].
In two children, the disease presented prenatally: one male was born at 26 weeks' gestation following preterm labor resulting from polyhydramnios that was believed to be due to hypotonia and decreased fetal movement [van Rij et al 2016]; another male was delivered at 34 weeks' gestation due to prenatally diagnosed supraventricular tachycardia [Dai et al 2017].
The common clinical manifestations summarized in Table 2 are discussed below the table.
Table 2.
Clinical Manifestations of FBXL4-Related Mitochondrial DNA Depletion Syndrome
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Clinical Manifestation | Frequency |
---|
Neurologic
|
50/50 (100%)
|
Developmental delay Hypotonia Seizures Movement disorders 1 Ataxia Autonomic dysfunction Stroke-like episodes
| 45/45 (100%) 39/42 (93%) 14/42 (33%) 5/17 (29%) 4/15 (27%) 3/12 (25%) 1/32 (3%)
|
Growth
| |
| 25/33 (76%) 18/31 (58%) 17/31 (55%) 14/36 (39%)
|
Gastrointestinal
| |
Feeding difficulties Hepatopathy
|
|
Cardiac
|
20/37 (54%)
|
| 10/37 (27%) 7/37 (19%) 6/41 (15%) 4/37 (11%)
|
Ophthalmologic
|
20/30 (67%)
|
Cataract Strabismus Nystagmus Optic atrophy
| 5/30 (17%) 5/31 (16%) 6/30 (20%) 3/30 (10%)
|
Other
| |
Neutropenia Hearing impairment
|
|
IUGR = intrauterine growth restriction, defined as birth weight <10th centile
- 1.
Neurologic. Developmental delay is usually global, associated with severe speech impairment and lack of ambulation in the majority of reported cases. All affected individuals alive at the time they were reported (age range: 1 month – 36 years; median age: 3.5 years) demonstrated significant developmental delay [Gai et al 2013, Huemer et al 2015, Antoun et al 2016, Barøy et al 2016, Pronicka et al 2016, Dai et al 2017].
Hypotonia is severe and early onset, often presenting in the neonatal period.
Seizures started at age four months in one infant [Dai et al 2017]. Seizure types reported include complex partial seizures [Barøy et al 2016] and absence and generalized seizures [Gai et al 2013].
Other less commonly reported neurologic manifestations for which clinical information is available include:
Gastrointestinal manifestations. Feeding difficulties are a major problem for most individuals with FBXL4-related mtDNA depletion syndrome. Factors contributing to the feeding difficulties include hypotonia, gastroesophageal reflux disease, frequent vomiting, and swallowing dysfunction. Recurrent aspiration was reported in six individuals [Gai et al 2013]. Many require nasogastric tube feeding or gastrostomy.
Hepatopathy manifests as mildly elevated transaminases. Liver failure has not been reported to date. Of note, one individual with baseline mild increases in transaminases experienced further increase in liver enzymes following initiation of a ketogenic diet (initiated due to initial suspicion of pyruvate dehydrogenase deficiency) [Barøy et al 2016].
Cardiac. Cardiomyopathy, the most common cardiac manifestation, is typically hypertrophic. Left ventricular non-compaction was reported in one individual [Huemer et al 2015].
Congenital heart malformations include atrial septal defect, ventricular septal defect, patent foramen ovale, patent ductus arteriosus, tricuspid regurgitation, and tetralogy of Fallot (TOF). Other than TOF, the reported cardiac malformations are either relatively common or physiologic, bringing into question whether these are true associations or chance occurrences.
Arrhythmias include supraventricular tachycardia and Wolff-Parkinson-White syndrome [Antoun et al 2016, Barøy et al 2016, Dai et al 2017].
Ophthalmologic. Cataract was congenital in three individuals [Bonnen et al 2013, Gai et al 2013, Huemer et al 2015].
Other reported eye findings include nystagmus and optic atrophy [Huemer et al 2015, Morton et al 2017].
Immunologic. Neutropenia was either episodic or persistent. Neutropenia appeared to predispose to infections and poor wound healing [Huemer et al 2015].
One individual had lymphopenia and hypogammaglobulinemia in addition to neutropenia [Antoun et al 2016].
Even without neutropenia, some individuals were prone to recurrent infections which in some cases resulted in metabolic decompensation and death [Bonnen et al 2013, Gai et al 2013].
Distinctive facial features. About 70% of affected individuals have some variable distinctive facial features, including the following: thick eyebrows, short, upslanted palpebral fissures with epicanthus, broad nasal bridge, bulbous nasal tip, and smooth and long philtrum.
Less frequently reported manifestations
Other uncommon features include renal tubular acidosis (5 individuals), progressive scoliosis (2 individuals), non-specified exercise intolerance (4 individuals), and sleep dysfunction.
Several males had hypospadias and/or cryptorchidism. One male had hypoplastic scrotum [
Huemer et al 2015].
One individual developed exocrine pancreatic deficiency [
Gai et al 2013].
Prognosis.
FBXL4-related mtDNA depletion syndrome is associated with a high rate of death in childhood: 43% (20 of 47) of reported children are deceased; seven died early in infancy. The median age of death was two years (range 2 days – 75 months). The 27 individuals alive at the time that they were reported ranged in age from one month to 36 years (median age: 3.5 years). Because of the small number of reported individuals, it is possible (indeed, likely) that the published literature is biased towards more severe cases and, thus, the full clinical spectrum (and prognosis) is yet to be appreciated.