Fbxl4-Related Encephalomyopathic Mitochondrial Dna Depletion Syndrome
Summary
Clinical characteristics.
FBXL4-related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome is a multi-system disorder characterized primarily by congenital or early-onset lactic acidosis and growth failure, feeding difficulty, hypotonia, and developmental delay. Other neurologic manifestations can include seizures, movement disorders, ataxia, autonomic dysfunction, and stroke-like episodes. All affected individuals alive at the time they were reported (median age: 3.5 years) demonstrated significant developmental delay. Other findings can involve the heart (hypertrophic cardiomyopathy, congenital heart malformations, arrhythmias), liver (mildly elevated transaminases), eyes (cataract, strabismus, nystagmus, optic atrophy), hearing (sensorineural hearing loss), and bone marrow (neutropenia, lymphopenia). Survival varies; the median age of reported deaths was two years (range 2 days – 75 months), although surviving individuals as old as 36 years have been reported. To date FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals.
Diagnosis/testing.
The diagnosis of FBXL4-related mtDNA depletion syndrome is established in a proband by identification of biallelic pathogenic variants in FBXL4 on molecular genetic testing.
Management.
Treatment of manifestations: Management is best provided by a multidisciplinary team including neurology, nutrition, clinical genetics/metabolism, and developmental pediatrics. Other specialties may be involved as needed. To date no definite treatment is available; thus, treatment is mainly supportive: assuring adequate nutrition and standard treatment of neurologic complications including developmental delay / intellectual disability, seizures, cardiac complications, eye involvement, and hearing loss. Administration of cofactors and antioxidants, used in mitochondrial disorders with (generally) limited evidence of benefit, may be considered.
Surveillance: No surveillance guidelines have been published. The treating physician should decide about the frequency of follow up of eyes, hearing, heart, feeding difficulties, liver, neurologic complications, and neutropenia based on the patient's findings.
Genetic counseling.
FBXL4-related mtDNA depletion syndrome is inherited in an autosomal recessive manner. When both parents are heterozygous carriers, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier (heterozygote), and a 25% chance of being unaffected and not a carrier. Once the FBXL4 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
FBXL4-related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome should be suspected in individuals with early-onset (often congenital) lactic acidosis along with a combination of the following clinical features, brain MRI findings, and supportive laboratory findings.
Clinical features
- Developmental delay. Often global with severe speech impairment and lack of ambulation
- Neurologic findings, Hypotonia, seizures, movement disorders, such as ataxia, autonomic dysfunction
- Feeding difficulty and failure to thrive
- Abnormal growth. Intrauterine growth restriction, short stature, microcephaly (congenital and acquired)
- Cardiovascular abnormalities. Hypertrophic cardiomyopathy, congenital heart malformations, arrhythmia, pulmonary hypertension
Brain MRI findings
- White matter abnormalities (19/32 individuals reported). T2-weighted hyperintensities, delayed or poor myelination, and leukodystrophic changes
- Cerebral atrophy (14/32). Progressive; could be evident as early as age three months [Bonnen et al 2013, Huemer et al 2015]
- Basal ganglia abnormalities, including lesions and abnormal signal intensities (11/32)
- Pervientricular cysts (9/32)
- Thin corpus callosum (6/32)
- Cerebellar hypoplasia (6/32)
- Arachnoid cysts (4/32)
- Brain stem atrophy (4/32)
- Stroke-like episodes (1/32) [Ebrahimi-Fakhari et al 2015]
Only one child (who died at age 20 months) was reported to have a normal brain MRI [Bonnen et al 2013].
MR spectroscopy may show high lactate peak in the brain and cerebrospinal fluid [Bonnen et al 2013, Antoun et al 2016, Barøy et al 2016, Dai et al 2017].
Supportive laboratory findings
- Persistently elevated lactate levels (range: 3-21 mmol/L; median: 13 mmol/L) were observed in all individuals. When assayed, cerebrospinal fluid lactate levels were also elevated [Huemer et al 2015, Barøy et al 2016, Dai et al 2017].
- Hyperammonemia is seen in about 50% of individuals. Although ammonia levels close to 500 μmol/L have been reported [Dai et al 2017], the mean level was 141 μmol/L, median level 99 μmol/L, and range 30-485 μmol/L.
- Mild to moderate elevations in creatine kinase were reported in six of 13 individuals in one study [Huemer et al 2015].
- Muscle tissue and skin fibroblasts show [Bonnen et al 2013, Gai et al 2013, Huemer et al 2015, Antoun et al 2016, Barøy et al 2016, Pronicka et al 2016, Dai et al 2017, Morton et al 2017]:
- Variably reduced mtDNA content (range: 10%-70%; mean: ~30% of tissue- and age-matched controls); and
- Decreased activity of multiple complexes on electron transport chain activity assay in 80% of affected individuals. There is usually combined, though variable, deficiency of all complexes.
- Muscle histology can show fiber size variability, lipid and glycogen accumulation, and variable reduction in COX activity. Enlarged and structurally altered mitochondria can be seen on electron microscopy [Bonnen et al 2013, Gai et al 2013, Huemer et al 2015, Antoun et al 2016, Barøy et al 2016, Dai et al 2017].
Establishing the Diagnosis
The diagnosis of FBXL4-related mtDNA depletion syndrome is established in a proband by identification of biallelic pathogenic variants in FBXL4 on molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel or single-gene testing) and genomic testing (comprehensive genome sequencing) depending on the phenotype.
Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Children with the suggestive clinical, laboratory, and neuroimaging findings could be diagnosed using gene-targeted testing (see Option 1), whereas those with clinical features indistinguishable from many other mitochondrial disorders are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the clinical, laboratory, and brain MRI findings suggest the diagnosis of FBXL4-related mtDNA depletion syndrome, molecular genetic testing approaches can include single-gene testing and use of a multigene panel:
- Single-gene testing. Sequence analysis of FBXL4 is performed first. If only one pathogenic variant is found, gene-targeted deletion/duplication analysis could be considered; however, to date no exon or whole-gene deletions have been reported.
- A multigene panel that includes FBXL4 and other genes related to mtDNA depletion syndromes (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. Of note, given the rarity of FBXL4-related mtDNA depletion syndrome some panels for mtDNA depletion syndromes may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) 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.
Option 2
When the phenotype is indistinguishable from many other mitochondrial disorders molecular genetic testing approaches can include a combination of genomic testing (comprehensive genome sequencing) or gene-targeted testing (multigene panel):
- Comprehensive genomic testing (when available) includes exome sequencing and genome sequencing [Wortmann et al 2015, Pronicka et al 2016].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.
Gene 1 | Method | Proportion of Probands with Pathogenic Variants 2 Detectable by Method |
---|---|---|
FBXL4 | Sequence analysis 3 | 50/50 4 |
Gene-targeted deletion/duplication analysis 5 | None reported to date |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
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]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Clinical Characteristics
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 Manifestation | Frequency |
---|---|
Neurologic | 50/50 (100%) |
|
|
Growth | |
|
|
Gastrointestinal | |
|
|
Cardiac | 20/37 (54%) |
|
|
Ophthalmologic | 20/30 (67%) |
|
|
Other | |
|
|
IUGR = intrauterine growth restriction, defined as birth weight <10th centile
- 1.
Movement disorders reported include dystonia, choreoathetosis, hyperkinetic movements, and tremors [Gai et al 2013, Barøy et al 2016, Pronicka et al 2016].
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:
- Movement disorders including hyperkinetic movements [Barøy et al 2016], dystonia and choreoathetosis [Gai et al 2013], and tremors [Pronicka et al 2016];
- Recurrent stroke-like episodes starting at age ten years in a girl who was reported at age 13 years [Ebrahimi-Fakhari et al 2015, Huemer et al 2015].
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
- Respiratory distress, likely due to hypotonia and weak muscles, was reported in six individuals [Gai et al 2013, Dai et al 2017].
- Sensorineural hearing impairment was reported in four individuals [Huemer et al 2015, Barøy et al 2016, Dai et al 2017, Morton et al 2017].
- 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.
Genotype-Phenotype Correlations
No genotype-phenotype correlations are known.
Prevalence
FBXL4-related mtDNA depletion syndrome is rare; the exact prevalence is unknown.
To date, 50 affected individuals from different ethnic groups – including Arabs, persons of northern European heritage, and Latin Americans/Hispanics – have been reported [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].
Consanguinity was reported in 64% of cases.
Differential Diagnosis
FBXL4-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.
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). The function of FBXL4 is not yet known.
Mitochondrial DNA depletion syndromes are phenotypically classified into myopathic, encephalomyopathic, hepatocerebral, and neurogastrointestinal forms (Table 3) [El-Hattab & Scaglia 2013].
Myopathic forms present in infancy or early childhood with hypotonia, proximal muscle weakness, and feeding difficulty. Cognition is usually spared. Typically, there is rapid progression of muscle weakness with respiratory failure and death within a few years of onset.
Encephalomyopathic mtDNA depletion syndromes present in infancy with hypotonia and developmental delay. Depending on the underlying defect, other features, including deafness, movement disorders, Leigh like syndrome, and renal disease, can be observed.
Hepatocerebral forms present with early-onset liver dysfunction and neurologic involvement, including developmental delay, abnormal eye movements, and peripheral neuropathy.
Neurogastrointestinal forms, the prototype of which is mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease, present in adolescence to early adulthood with progressive gastrointestinal dysmotility, cachexia, and peripheral neuropathy.
Table 3.
Phenotype 1 | Gene | Mitochondrial DNA Depletion Syndrome #, Type | Reference 2 |
---|---|---|---|
Hepato- cerebral | DGUOK | 3, hepatocerebral type | Deoxyguanosine Kinase Deficiency |
POLG | 4A, Alpers type | POLG-Related Disorders | |
MPV17 | 6, hepatocerebral type | MPV17-Related Hepatocerebral Mitochondrial DNA Depletion Syndrome | |
TWNK (C10orf2) | 7, hepatocerebral type | OMIM 271245 | |
TFAM | 15, hepatocerebral type | OMIM 617156 | |
Encephalo- myopathic | SUCLA2 | 5, encephalomyopathic type w/methylmalonic aciduria | SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria |
FBXL4 | 13, encephalomyopathic type | FBXL4-Related Encephalomyopathic Mitochondrial DNA Depletion Syndrome | |
SUCLG1 | 9, encephalomyopathic type with methylmalonic aciduria | SUCLG1-Related mtDNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria | |
RRM2B | 8A, encephalomyopathic type w/renal tubulopathy | RRM2B-Related Mitochondrial Disease | |
OPA1 | 14, encephalocardiomyopathic type | OMIM 616896 | |
ABAT | Encephalomyopathic type | OMIM 613163 | |
Neurogastro- intestinal | TYMP | 1, MNGIE type | Mitochondrial Neurogastrointestinal Encephalopathy Disease |
POLG | 4B, MNGIE type | POLG-Related Disorders | |
RRM2B | 8B, MNGIE type | RRM2B-Related Mitochondrial Disease | |
Myopathic | TK2 | 2, myopathic type | TK2-Related Mitochondrial DNA Depletion Syndrome, Myopathic Form |
AGK | 10, cardiomyopathic type (Sengers syndrome) | OMIM 212350 | |
MGME1 | 11, myopathic type | OMIM 615084 | |
SLC25A4 | 12B, cardiomyopathic type | OMIM 615418 |
- 1.
Within each phenotypic category, mtDNA depletion syndromes are ordered by relative prevalence.
- 2.
See hyperlinked GeneReview or OMIM phenotype entry for more information.
Management
Evaluations Following Initial Diagnosis
To establish the extent of the disease and needs in an individual diagnosed with FBXL4-related mtDNA depletion syndrome, the evaluations following diagnosis (if not performed as part of the evaluation that led to diagnosis) listed in Table 4 are recommended.
Table 4.
System/Concern | Evaluation | Comment |
---|---|---|
Eyes | Ophthalmologic eval | |
ENT | Hearing assessment | |
Cardiovascular | Cardiac eval w/EKG & echocardiography | Consider referral to cardiologist if results are abnormal. |
Gastrointestinal | Nutritional eval; swallowing assessment for feeding difficulties | |
Eval of liver function w/AST/ALT, bilirubin, total protein, albumin, & coagulation profile | ||
Neurologic |
| |
Electroencephalogram | If history of seizures | |
Immunologic | Complete blood count to evaluate for neutropenia | Consider more detailed immunologic eval if history of recurrent infections. |
Miscellaneous/ Other | Developmental eval to provide baseline level of functioning & recommendations for services (speech, occupational, & physical therapy) | |
Consultation w/clinical geneticist &/or genetic counselor |
Treatment of Manifestations
Management is best provided by a multidisciplinary team including neurology, nutrition, clinical genetics / metabolism, and developmental pediatrics. Other specialties including gastroenterology, cardiology, hematology, immunology, ophthalmology, and nephrology may be involved based on the associated complications.
No definite treatment is available to date; thus, treatment is mainly supportive (Table 5). Administration of cofactors and antioxidants, used in mitochondrial disorders with (generally) limited evidence of benefit, may be considered.
Table 5.
Manifestation/Concern | Treatment | Considerations/Other |
---|---|---|
Inadequate nutrition | A nasogastric tube or gastrostomy tube are frequently needed |