Serac1 Deficiency
Summary
Clinical characteristics.
The phenotypic spectrum of SERAC1 deficiency comprises MEGD(H)EL syndrome (3-methylglutaconic aciduria with deafness-dystonia, [hepatopathy], encephalopathy, and Leigh-like syndrome), juvenile-onset complicated hereditary spastic paraplegia (in 1 consanguineous family), and adult-onset generalized dystonia (in 1 adult male). MEGD(H)EL syndrome is characterized in neonates by hypoglycemia and a sepsis-like clinical picture for which no infectious agent can be found. During the first year of life feeding problems, failure to thrive, and/or truncal hypotonia become evident; many infants experience (transient) liver involvement ranging from undulating transaminases to prolonged hyperbilirubinemia and near-fatal liver failure. By age two years progressive deafness, dystonia, and spasticity prevent further psychomotor development and/or result in loss of acquired skills. Affected children are completely dependent on care for all activities of daily living; speech is absent.
Diagnosis/testing.
The diagnosis of SERAC1 deficiency is established in a proband with suggestive clinical and metabolic (3-methylglutaconic aciduria) findings and biallelic pathogenic variants in SERAC1 identified by molecular genetic testing.
Management.
Treatment of manifestations: Treatment of MEGD(H)EL syndrome is supportive. Care is best provided by a multidisciplinary team including a metabolic pediatrician, pediatric neurologist, dietician, and physical therapist when possible. Some individuals have experienced (temporary) improvement of spasticity with oral or intrathecal baclofen treatment. Respiratory problems resulting from excessive drooling improve with botulinum toxin injection in the salivary glands, extirpation of salivary glands, and/or rerouting of glandular ducts. An age-appropriate diet given via nasogastric tube or gastrostomy can greatly improve overall clinical condition.
Surveillance: Neurologic and orthopedic evaluations as needed based on individual findings are appropriate.
Genetic counseling.
SERAC1 deficiency 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. Once the SERAC1 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
SERAC1 deficiency should be suspected in an individual with: one of the three main clinical phenotypes defined within the SERAC1 deficiency spectrum; characteristic imaging findings; and autosomal recessive family history.
Three Main Clinical Phenotypes
1. Infantile, severe MEGD(H)EL syndrome (3-methylglutaconic aciduria with deafness-dystonia, [hepatopathy], encephalopathy, and Leigh-like syndrome):
- Transient hypoglycemia
- Sepsis-like episodes without infection
- Transient liver involvement ranging from undulating elevation of transaminases to prolonged hyperbilirubinemia and hyperammonemia and near-fatal liver failure
- Feeding problems
- Failure to thrive
- Optic atrophy
- Developmental delay followed by motor and cognitive regression
- Progressive sensorineural hearing loss
- Progressive dystonia
- Progressive spasticity
- Laboratory findings:
- Elevated urinary concentration of 3-methylglutaconic acid (3-MGA) and 3-methylglutaric acid (3-MGC) on routine analysis of urine organic acids (see Table 1).
- Serum lactate concentration and serum alanine concentration can be elevated; serum cholesterol concentration may be decreased [Wortmann et al 2006, Wortmann et al 2012b, Sarig et al 2013, Tort et al 2013].
Table 1.
Urinary Concentration of 3-MGA in MEGD(H)EL Syndrome
| Phenotype | Urinary Concentration of 3-MGA (mmol/mol creatinine) |
|---|---|
| MEGD(H)EL syndrome | 16-196 |
| Normal controls | <10 1 |
Wortmann et al [2012b]
- 1.
Reference range as used at the Laboratory for Genetic Endocrine and Metabolic Diseases (LGEM), Department of Laboratory Medicine, Radboud UMC Nijmegen, Nijmegen, the Netherlands
2. Juvenile-onset complicated hereditary spastic paraplegia (described in a single consanguineous family) [Roeben et al 2018]:
- Cognitive delay
- Spasticity manifesting as slowly progressive lower limb spasticity beginning in adolescence
- Laboratory findings: 3-MGA excretion
3. Adult-onset generalized dystonia (single case) [Giron et al 2018]:
- Cognitive delay
- Progressive generalized hyperkinetic movement disorder beginning in early adulthood (3rd decade)
- Laboratory findings: variable degree of 3-MGA excretion
Brain MRI
Bilateral basal ganglia involvement is seen on brain MRI (comparable to Leigh syndrome) [Wortmann et al 2015]. All affected individuals with MEGD(H)EL syndrome had a distinctive brain MRI pattern with five characteristic disease stages affecting the basal ganglia, especially the putamen.
- Stage 0. Normal MRI
- Stage 1. T2-weighted signal changes present in the pallidum
- Stage 2. Swelling of the putamen and caudate nucleus. The dorsal putamen contains an "eye" that shows no signal alteration and (thus) seems to be spared during this stage of the disease.
- Stage 3. The putaminal eye increases, reflecting progressive putaminal involvement. This "eye" was found in all individuals with MEGD(H)EL syndrome during a specific age range (>1-4 years), and has not been reported in other disorders, making it pathognomonic for MEGD(H)EL syndrome and allowing diagnosis based on MRI findings.
- Stage 4. Basal ganglia degeneration until near loss; cortical and cerebellar atrophy
Family History
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
Establishing the Diagnosis
The diagnosis of SERAC1 deficiency is established in a proband with suggestive clinical and metabolic (3-methylglutaconic aciduria [3-MGA-uria]) findings and biallelic pathogenic variants in SERAC1 identified by molecular genetic testing (see Table 2).
Note: Identification of biallelic SERAC1 variants of uncertain significance (or identification of one known SERAC1 pathogenic variant and one SERAC1 variant of uncertain significance) does not establish or rule out a diagnosis of this disorder.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive laboratory findings described in Suggestive Findings (see Table 1) are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of SERAC1 deficiency has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
Single-gene testing. Sequence analysis of SERAC1 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
A spasticity, dystonia, deafness, nuclear mitochondrial, or intellectual disability multigene panel that includes SERAC1 and other genes of interest (see Differential Diagnosis) 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. 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. Of note, given the rarity of SERAC1 deficiency, some panels for spasticity, dystonia, deafness, nuclear mitochondrial, or intellectual disability 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
Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 2.
Molecular Genetic Testing Used in SERAC1 Deficiency
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| SERAC1 | Sequence analysis 3 | ~99% 4 |
| Deletion/duplication analysis 5 | ~1% 6 |
- 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. 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.
Wortmann et al [2012b], Sarig et al [2013], Tort et al [2013], Maas 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.
- 6.
A deletion of exons 5-8 has been reported [Maas et al 2017].
Clinical Characteristics
Clinical Description
To date, SERAC1 deficiency has been identified in more than 67 individuals with MEGD(H)EL syndrome (3-methylglutaconic aciduria with deafness-dystonia, [hepatopathy], encephalopathy, and Leigh-like syndrome) [Maas et al 2017, Giron et al 2018, Roeben et al 2018], one consanguineous family with juvenile-onset complicated hereditary spastic paraplegia [Roeben et al 2018], and one man with adult-onset generalized dystonia [Giron et al 2018]. The following descriptions of the phenotypic features associated with SERAC1 deficiency are based on these reports.
Table 3.
Select Features of SERAC1 Deficiency
| Feature | % of Persons w/Feature | Comment |
|---|---|---|
| Muscular hypotonia | 91% | |
| Moderate-to-severe intellectual disability | 88% |
|
| Progressive spasticity | 81% | |
| Dystonia | 81% | |
| Sensorineural hearing loss | 80% | |
| Loss of skills | 75% | |
| Neonatal liver dysfunction | 52% | |
| Neonatal hypoglycemia | 49% | |
| Seizures | 38% | Febrile seizures, myoclonic epilepsy |
| Neonatal liver failure | 30% | |
| Optic atrophy | 25% |
Based on Maas et al [2017]
The following clinical findings of SERAC1 deficiency are based on the combined personal experience of the authors as well as published data [Maas et al 2017, Giron et al 2018, Roeben et al 2018].
Infantile, Severe MEGD(H)EL Syndrome
Most children with MEGD(H)EL syndrome present in the neonatal period with hypoglycemia and a sepsis-like clinical picture for which no infectious agent can be found. Several neonates with prolonged jaundice were reported.
During the first year of life affected infants often come to the attention of a physician because of feeding problems, failure to thrive, and/or truncal hypotonia. Liver involvement (ranging from cholestasis to hepatitis of unknown origin to fulminant liver failure) is also frequently seen but mostly transient.
By age two years the neurologic findings become more apparent. Progressive spasticity (as defined by increasing resistance to speed or angle with passive flexion as well as hypertonia and hyperreflexia) and dystonia either prevent further development or lead to loss of acquired skills. Speech is often completely absent, leading to investigation and detection of progressive deafness.
The further clinical course is slowly progressive. Affected children are completely dependent on care for all activities of daily living: they are unable to sit independently and are wheelchair bound and nonambulatory. Scoliosis and/or contractures may require bracing.
Communication is limited to the expression of comfort and discomfort; speech is absent.
Feeding is complicated by the movement disorder and often also by excessive drooling, often requiring tube feeding.
Some affected individuals have epilepsy which occurs either in the neonatal period or later in the disease course.
The length of survival varies. Some do not survive the neonatal period due to multiorgan failure, some succumb to liver failure in infancy, and others to (pulmonary) infections later in life. The oldest living affected individual is older than age 24 years.
Milder Juvenile-Onset Complicated Hereditary Spastic Paraplegia (cHSP)
Juvenile-onset paraspasticity, complicated by nonprogressive mild cognitive deficits, was observed in one family in which five of six affected sibs were homozygous for the splice site variant c.91+6T>C [Roeben et al 2018].
- Three had a relatively benign cHSP disease course. Cognitive delay was detected at school age. None had a history of infantile feeding problems, liver failure, hearing loss, or truncal hypotonia. All were still able to walk several miles without assistance at age ten to 20 years, and the youngest sib did not show any motor problems at age ten years.
- Only one of six, who was the most severely affected, showed signs of dystonia.
Adult-Onset Generalized Dystonia
A man age 31 years (compound heterozygous for c.1347-1350dupATCT [p.Val451fs] and c.1598C.T [p.Pro533Leu]) is the only person with SERAC1 deficiency with this phenotype described to date [Giron et al 2018]. He had a history of mild psychomotor delay, and was referred for evaluation of generalized dystonia with chorea-like movements at age 31 years. At age 24 years, he had had a few episodes of subacute encephalopathy triggered by fever; he subsequently developed cervical dystonia that gradually worsened, becoming generalized. He also developed progressive lower-limb spasticity and hyperkinetic dysarthria. These findings began with and worsened after episodes of fever. Brain MRI showed bilateral shrunken striata, suggestive of Leigh syndrome. Electromyography showed severe axonal neuropathy. Visual evoked potentials revealed bilateral optic neuropathy. Audiograms were normal.
Genotype-Phenotype Correlations
Currently, no clear relationship exists between the type and position of the SERAC1 pathogenic variants and phenotype.
The level of 3-methylglutaconic aciduria does not correlate with the clinical course.
Prevalence
The prevalence of MEGD(H)EL syndrome is estimated at 0.09:100,000 [Tan et al 2020].
Differential Diagnosis
Differential diagnosis of 3-methylglutaconic aciduria (3-MGA-uria). Increased urinary excretion of the branched-chain organic acid 3-MGA (3-MGA-uria) is a relatively common finding in children investigated for suspected inborn errors of metabolism [Wortmann et al 2013b]. Inborn errors of metabolism with 3-MGA-uria as a discriminative feature (see Table 4) show a characteristic "syndromal" pattern of signs and symptoms [Wortmann et al 2013a, Wortmann et al 2013b, Kovacs-Nagy et al 2018]. The exact source of 3-MGA-uria is known only in AUH defect, the rarest type, caused by primary deficiency of the mitochondrial enzyme 3-methylglutaconyl-CoA hydratase resulting in blockage of leucine catabolism. The origin of the increased 3-MGA excretion in all other types is unknown, but mitochondrial dysfunction is thought to be the common denominator [Wortmann et al 2009].
Table 4.
Genes of Interest in the Differential Diagnosis of SERAC1 Deficiency
| Gene | Disorder | MOI | Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| 3-MGA-uria | Key clinical characteristics | |||
| ACTB | ACTB Baraitser-Winter cerebrofrontofacial syndrome w/juvenile-onset dystonia | AD | Absent | Deafness, dystonia, ID, DD |
| AGK | Sengers syndrome (See Mitochondrial DNA Maintenance Defects Overview.) | AR | Present * | Cataracts, cardiomyopathy, (DD 1) |
| ATAD3A | Harel-Yoon syndrome (OMIM 617183) | AD AR | Present * | Global DD, hypotonia, optic atrophy, axonal neuropathy, hypertrophic cardiomyopathy 2 |
| AUH | AUH defect (OMIM 250950) | AR | Present * | Adult-onset progressive spasticity & dementia w/characteristic slowly developing radiologic picture of extensive leukoencephalopathy 3, 4 |
| BCAP31 | Deafness, dystonia, & cerebral hypomyelination (OMIM 300475) | XL | Absent | Deafness, dystonia, ID, DD, cerebral hypomyelination |
| CLPB | CLPB deficiency | AR | Present * | Cataracts, central hypopnea, DD, ID, movement disorder, neutropenia, (epilepsy 1) |
| DNAJC19 | DNAJC19 defect (DCMA syndrome) (OMIM 610198) | AR | Present * | Characteristic combination of childhood-onset dilated cardiomyopathy, nonprogressive cerebellar ataxia, testicular dysgenesis, & growth failure |
| FITM2 | Siddiqi syndrome (OMIM 618635) | AR | Absent | Deafness, dystonia, ID, DD |
| HTRA2 | MGCA8 (OMIM 617248) | AR | Present * | Cataracts, central hypopnea, DD, ID, epilepsy, movement disorder, neutropenia |
| MICOS13 (C19orf70, QIL1) | Combined oxidative phosphorylation deficiency 37 (OMIM 618329) | AR | Present * | Hypotonia, failure to thrive, neurodegeneration w/loss of developmental milestones, liver dysfunction |
| OPA3 | Costeff syndrome | AR | Present * | Optic atrophy, movement disorder (ataxia or extrapyramidal disorder) |
| SUCLA2 | SUCLA2 mtDNA depletion syndrome, encephalomyopathic form w/methylmalonic aciduria | AR | May be present |
|
| TAZ | Barth syndrome | XL | Present * | In males, cardiomyopathy (left ventricular noncompaction), neutropenia, myopathy, typical facial features, hypocholesterolemia, & cognitive phenotype |
| TIMM50 | MGCA9 (OMIM 617698) | AR | Present * | DD, ID, epilepsy |
| TIMM8A | Deafness-dystonia-optic neuronopathy syndrome | XL | Absent 6 |
|
| TMEM70 | TMEM70 defect (OMIM 614052) | AR | Present * |
|
3-MGA-uria = 3-methylglutaconic aciduria; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
See also Kovacs-Nagy et al [2018], Table 1.
* 3-MGA-uria is a discriminative feature of this disorder.
- 1.
Seen in some affected persons
- 2.
Harel et al [2016]
- 3.
Wortmann et al [2010]
- 4.
AUH defect is the only one of the five inborn errors of metabolism with 3-MGA-uria with a distinct biochemical finding: elevated urinary excretion of 3-hydroxyisovaleric acid (3-HIVA).
- 5.
Increased C3- & C4-dicarboxyli-carnitine esters.
- 6.
Wortmann et al [2012a]
- 7.
The phenotypic spectrum of TMEM70 defect is variable and becoming broader as more affected individuals are reported. At this time no specific syndromic presentation is evident.
Mitochondrial disorders should also be considered in the differential diagnosis of SERAC1 deficiency. Mitochondrial disorders are caused by pathogenic variants in mitochondrial DNA or nuclear DNA and can present with any sign or symptom. Over 320 mitochondrial disorders have been identified [Wortmann et al 2017]. Tissues with higher requirements for oxidative metabolism, such as the central nervous system and cardiac and skeletal muscle, are predominantly affected.
3-MGA-uria is common in mitochondrial disorders [Wortmann et al 2012a], although 3-MGA excretion is lower than in MEGD(H)EL syndrome, and clinical features observed in MEGD(H)EL syndrome are frequently found in mitochondrial disorders. For example: progressive deafness is often reported with the mitochondrial DNA pathogenic variant m.3243A>G; and Leigh syndrome and dystonia are a typical neuro(radio)logic finding in mitochondrial disorders in relation to deficiency of complex I or IV of the respiratory chain. SERAC1 deficiency can be distinguished from mitochondrial disorders by the distinctive combination of deafness, spasticity, dystonia, and Leigh syndrome associated with MEGD(H)EL syndrome.
Other SERAC1 deficiency phenotypes. The phenotypic features associated with SERAC1 juvenile-onset complicated hereditary spastic paraplegia (cHSP) and SERAC1 adult-onset generalized dystonia are not sufficient to diagnose these conditions. All cHSP types with juvenile onset (see Hereditary Spastic Paraplegia Overview) and all types of adult-onset generalized dystonia (see Hereditary Dystonia Overview) should be considered in the differential diagnoses for these conditions.
Cerebral palsy. Slowly progressive spasticity and dystonia as seen in MEGD(H)EL syndrome may be misdiagnosed as cerebral palsy when deafness or abnormalities on brain MRI are not recognized. Therefore, the authors recommend that urinary organic acid analysis be performed on individuals with atypical cerebral palsy.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SERAC1 deficiency, the evaluations summarized in Table 5