Clpb Deficiency
Summary
Clinical characteristics.
CLPB (caseinolytic peptidase B) deficiency is characterized by neurologic involvement and neutropenia, which range from severe to mild. To date, a total of 26 individuals from 16 families have been reported.
- In severe CLPB deficiency, death usually occurs at a few months of age as a result of significant neonatal neurologic involvement (hyperekplexia or absence of voluntary movements, hypotonia or hypertonia, swallowing problems, respiratory insufficiency, and epilepsy) and severe neutropenia associated with life-threatening infections.
- In moderate CLPB deficiency neurologic abnormalities in infancy are comparable to but less severe than those observed in the severe phenotype (e.g., hypotonia and feeding problems) and in later childhood can include spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability ranging from mild learning disability to limited development of all cognitive and motor functions. Neutropenia is variable, but not life threatening.
- In mild CLPB deficiency there is no neurologic involvement, intellect is normal, and neutropenia is mild and intermittent. Life expectancy is normal.
Diagnosis/testing.
The diagnosis of CLPB deficiency is established in a proband with one or more suggestive clinical and/or imaging findings and/or elevated urinary excretion of 3-methylglutaconic acid (3-MGA), and identification of biallelic pathogenic variants in CLPB on molecular genetic testing.
Management.
Treatment of manifestations: Treatment is largely supportive. A multidisciplinary team including a metabolic physician, pediatric neurologist, developmental pediatrician, dietitian, physical therapist, and rehabilitation specialist is recommended. No specific dietary or metabolic treatment is available. Thorough developmental assessment is indicated for all children with cognitive difficulties to tailor special education services. Early intervention may include physical therapy, occupational therapy, and/or speech therapy. Treatment of the neurologic manifestations is per current clinical practice based on the findings. Granulocyte-colony stimulating factor (G-CSF) can be used to increase neutrophil counts to reduce the frequency of infections, especially in individuals with the mild or moderate phenotype.
Surveillance: Neurologic, ophthalmologic, immunologic/hematologic, and orthopedic evaluations are based on individual findings as needed.
Agents/circumstances to avoid: Drugs potentially toxic to mitochondria, including chloramphenicol, aminoglycosides, linezolide, valproic acid, and nucleoside reverse transcriptase inhibitors.
Genetic counseling.
CLPB 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 CLPB pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic diagnosis are possible.
Diagnosis
Suggestive Findings
CLPB (caseinolytic peptidase B) deficiency should be suspected in individuals with the following clinical, laboratory, and imaging findings.
Clinical findings. The disease spectrum of CLPB deficiency ranges from severe to mild. Findings by phenotype:
- All phenotypes. Congenital or infantile cataracts
- Severe phenotype
- Neonates. Hyperekplexia, absence of voluntary movements, respiratory insufficiency, and swallowing problems
- Neonates or infants. Microcephaly
- Moderate and severe phenotypes
- Infants. Ataxia, tremor and dystonia, dyskinesia
- After infancy. Intellectual ability which can range from normal to severe intellectual disability (with virtually no development), and muscular hypotonia which can progress to spasticity
Laboratory findings
- Neutropenia beginning at birth can be chronic or intermittent (especially during infections) with absolute neutrophil count (ANC) ranging from severe to mild:
- Severe. ANC <0.5 per mm3
- Moderate. ANC <1.0 per mm3
- Mild. ANC <1.5 per mm3
- Elevated urinary excretion of 3-methylglutaconic acid (3-MGA) (typically 2-10x the reference range) has been observed in all affected individuals to date.Note: (1) Each laboratory has its own reference range; for example, in the authors' laboratory, normal is <20 mmol/mol creatinine. (2) The value can vary between samples from the same individual.
Imaging findings. Initial brain MRI is often unremarkable; however, during infancy progressive cerebral and cerebellar atrophy are seen on follow-up MRI in the majority of affected individuals [Wortmann et al 2015] (full text).
Establishing the Diagnosis
The diagnosis of CLPB deficiency is established in a proband with:
- One or more suggestive clinical and/or imaging findings;AND/OR
- Elevated urinary excretion of 3-methylglutaconic acid (3-MGA);AND
- Identification of biallelic pathogenic variants in CLPB 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 genomic sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing may not. Because the phenotype of CLPB deficiency is broad, children with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a mild phenotype indistinguishable from many other inherited disorders with intellectual disability and neurologic findings or neutropenia are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of CLPB deficiency, molecular genetic testing approaches can include single-gene testing and use of a multigene panel:
- Single-gene testing. Sequence analysis of CLPB 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 CLPB and other genes of interest (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 likley 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. (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 inherited disorders with intellectual disability and neurologic findings or neutropenia, molecular genetic testing approaches can include genomic testing (comprehensive genomic sequencing; recommended) and/or gene-targeted testing (multigene panel; to consider).
Recommended testing. Comprehensive genomic sequencing (when available) including exome sequencing and genome sequencing may be considered if the phenotype alone is insufficient to support gene-targeted testing. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Testing to consider. A multigene panel that includes CLPB and other genes of interest (see Differential Diagnosis) may be considered; however, given the rarity of CLPB deficiency many multigene panels for intellectual disability and/or this complex neurologic phenotype or neutropenia may not include this gene.
Table 1.
Molecular Genetic Testing Used in CLPB Deficiency
| Gene 1 | Method | Proportion of Probands with Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| CLPB | Sequence analysis 3 | 16/16 4 |
| Gene-targeted deletion/duplication analysis 5 | Unknown 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.
Capo-Chichi et al [2015], Kanabus et al [2015], Saunders et al [2015], Wortmann et al [2015], Kiykim et al [2016]
- 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.
No deletions or duplications involving CLPB have been reported.
Clinical Characteristics
Clinical Description
The disease spectrum of CLPB deficiency ranges from severe to moderate to mild as determined by neurologic involvement and neutropenia. Children with neonatal onset or early-infantile onset have severe involvement and may die from complications of their disease, whereas those with late-infantile and early-childhood onset have a milder clinical presentation [Wortmann et al, unpublished data].
While many, but not all, individuals with CLPB deficiency have bilateral congenital or infantile cataracts, their presence is not associated with the severity of the neurologic involvement or neutropenia.
Although no typical dysmorphic features have been reported, secondary dysmorphic features due to muscle involvement and movement disorder can be seen.
To date a total of 26 individuals from 16 families with CLPB deficiency have been reported in the literature (n=14 [Wortmann et al 2015], n=5 [Saunders et al 2015], n=4 [Capo-Chichi et al 2015], n=2 [Kanabus et al 2015], and n=1 [Kiykim et al 2016]). Most have been identified as neonates; all were symptomatic by early childhood.
Severe Phenotype
Neurologic. Affected infants come to attention at birth with significant neurologic involvement that can include hyperekplexia or absence of voluntary movements, hypotonia or hypertonia, swallowing problems, respiratory insufficiency, microcephaly (15/23 individuals), and epileptic seizures (with a burst suppression pattern on EEG). All affected infants require neonatal intensive care.
These infants show no motor or intellectual development, and generally die in the first months of life.
Retrospectively, many mothers of infants with the severe phenotype reported issues during the pregnancy, including decreased or increased fetal movements and intrauterine growth restriction [Wortmann et al, unpublished data].
Neutropenia. All infants with the severe phenotype had chronic, severe congenital neutropenia (ANC <500 per mm3) associated with life-threatening infections. Several affected infants progressed to a myelodysplastic syndrome / leukemia-like condition within the first months of life.
Moderate Phenotype
Neurologic. The neonatal course is often complicated by adaptive problems in the broadest sense as well as neurologic abnormalities that are comparable to but less severe than those observed in the severe phenotype (e.g., hypotonia and feeding problems).
Subsequent neurologic involvement varies. In many with neonatal onset generalized hypotonia progresses during childhood to spasticity (mainly of the legs). Many have an infantile-onset progressive movement disorder that can include ataxia, dystonia, or dyskinesia of varying severity. Several have epileptic seizures. All but two have intellectual disability that ranges from mild learning disability to very limited development of all cognitive and motor functions.
Neutropenia with varying ANC is common. Some affected individuals are only neutropenic during infections and some have recurrent (although not life-threatening) infections, including in the neonatal period.
Other. Many show biochemical evidence of endocrine abnormalities (e.g., hypothyroidism).
Mild Phenotype
Mildly affected individuals show only some clinical signs and symptoms without progression and survive without significant disease burden into adulthood.
Neurologic. There is no neurologic involvement; intellect is normal.
Neutropenia is mild and intermittent without increased risk of infection.
Other findings. Nephrocalcinosis and renal cysts without associated medical complications have been described in two individuals with the mild phenotype [Kanabus et al 2015].
Genotype-Phenotype Correlations
The study of genotype-phenotype correlations is hampered by the small number of individuals with CLPB deficiency. The number of patients sharing the same genotype is low.
An overview of all reported affected individuals revealed preliminary evidence in support of a genotype-phenotype correlation: individuals with the most severe phenotypes often have pathogenic variants predicted to lead to the complete absence of functional protein.
Nomenclature
CLPB deficiency may also be referred to as CLPB defect [Wortmann et al 2013a, Capo-Chichi et al 2015, Kanabus et al 2015, Saunders et al 2015, Wortmann et al 2015].
In OMIM 616271, CLPB deficiency is referred to as 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MEGCANN).
Prevalence
CLPB deficiency is rare. A total of 26 individuals with CLPB deficiency have been reported to date (n=14 [Wortmann et al 2015], n=5 [Saunders et al 2015], n=4 [Capo-Chichi et al 2015], n=2 [Kanabus et al 2015], n=1 [Kiykim et al 2016]). The affected individuals reported are of European, North American, and Asian ancestry.
In the largely Inuit population of Greenland the carrier frequency of the c.803C>T variant was determined to be 3.3%, which is comparable to carrier frequencies of other founder variants in Greenland.
Differential Diagnosis
Table 2. Disorders to Consider in the Differential Diagnosis of CLPB Deficiency
| Discriminative Feature | Disorder | Gene(s) | MOI | Additional Hallmarks 1 of the Disorder |
|---|---|---|---|---|
| 3-MGA-uria 2 | TAZ defect (Barth syndrome) | TAZ | XL | In affected males: growth delay in infancy, cardiomyopathy (left ventricular non-compaction), neutropenia, myopathy, typical facial features, hypocholesterolemia, & a cognitive phenotype |
| OPA3 defect (Costeff syndrome; OPA3-related 3-methylglutaconic aciduria) | OPA3 | AR | In infants: optic atrophy & movement disorder (ataxia or extrapyramidal disorder) | |
| SERAC1 defect (MEGDEL syndrome) | SERAC1 | AR | Neonatal hypoglycemia & liver failure 3 In 2nd yr of life: progressive SNHL & neurologic manifestations (truncal hypotonia, spasticity of the limbs, dystonia, severe ID/DD, Leigh syndrome-like findings on MRI) | |
| TMEM70 defect (OMIM 614052) | TMEM70 | AR | To date no specific syndromic presentation Typically in neonates: hyperammonemia, lactic acidosis, muscular hypotonia, hypertrophic cardiomyopathy, psychomotor retardation In individuals surviving neonatal period: DD | |
| DNAJC19 defect (DCMA syndrome) (OMIM 610198) | DNAJC5 | AR | Characteristic combination of childhood-onset dilated cardiomyopathy, non-progressive cerebellar ataxia, testicular dysgenesis, growth failure | |
| AUH defect (3-methylglutaconyl-CoA hydratase deficiency) (OMIM 250950) | AUH | AR | Adult-onset progressive spasticity & dementia w/characteristic slowly developing radiologic picture of extensive leukoencephalopathy 4 Uniquely distinguished by ↑ urinary excretion of 3-hydroxyisovaleric acid (3-HIVA) | |
| AGK defect (Sengers syndrome) (OMIM 212350) | AGK | AR | Characteristic combination of bilateral cataracts, hypertrophic cardiomyopathy, & no to mild ID Can be lethal in neonatal period but survivors to adulthood w/mild involvement are known | |
| Not otherwise specified 3-MGA-uria (former 3-MGCA 4) | Unknown | Normal 3-methylglutaconyl-CoA hydratase enzyme activity & no defect in TAZ, OPA3, SERAC1, TMEM70, DNAJC5, AUH, or AGK | ||
| Congenital neutropenia & cyclic neutropenia | ELANE-related neutropenia | ELANE | AD | Isolated neutropenia; no involvement of the CNS or other organs |
| G6PC3 deficiency | G6PC3 | AR | Presence of cardiovascular and/or urogenital abnormalities | |
| X-linked congenital neutropenia (see WAS-Related Disorders) | WAS | XL | Isolated neutropenia; no involvement of CNS or other organs | |
| GATA1-related X-linked cytopenia | GATA1 | XL | Typical presentation in affected males: bleeding disorder & anemia; neutropenia occurs later | |
| Shwachman-Diamond syndrome | SBDS | AR | Intestinal malabsorption due to exocrine pancreatic dysfunction | |
| Hyperekplexia | Hereditary hyperekplexia | ARHGEF9 GLRA1 GLRB GPHN SLC6A5 | AD AR XL | Generalized stiffness immediately after birth normalizes in 1st yrs of life. Unexpected (particularly auditory) stimuli cause excessive startle reflex (eye blinking, flexor spasm of the trunk), followed by short period of generalized stiffness during which voluntary movements are impossible. Neutropenia/severe infections, respiratory insufficiency, & swallowing problems are not seen in neonates; affected individuals improve over time. |
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; SNHL = sensorineural hearing loss; XL = X-linked
- 1.
In addition to discriminative feature shown in column 1
- 2.
Increased urinary excretion of 3-MGA, known as 3-methylglutaconic aciduria (3-MGA-uria), is a relatively common finding in children investigated for suspected inborn errors of metabolism [Wortmann et al 2013b]. The classification of inborn errors of metabolism with 3-MGA-uria as discriminative feature has recently been updated. Click here (pdf) [Wortmann et al 2013a].
- 3.
Sarig et al [2013]
- 4.
Wortmann et al [2010]
Click here (pdf) for information on classification of inborn errors of metabolism in which 3-methylglutaconic aciduria is a discriminative feature.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CLPB deficiency, the following evaluations are recommended:
- Complete physical examination
- Complete neurologic examination, including brain MRI (if not performed at the time of diagnosis)
- Developmental assessment or IQ testing (depending on the age of the individual at the time of diagnosis)
- For those with significant neurologic problems:
- Complete evaluation of feeding and diet to determine if tube feeding or gastrostomy is necessary
- Evaluation of excessive drooling to determine if the risk of aspiration and/or dehydration is increased
- Complete ophthalmologic examination to evaluate for cataracts (if not performed at the time of diagnosis)
- Absolute neutrophil count (ANC) is recommended to determine the need for granulocyte-colony stimulating factor (G-CSF) treatment.
- Ultrasound examination of the kidneys for evidence of nephrocalcinosis or cysts
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Treatment is supportive. Care is best provided by a multidisciplinary team including a metabolic pediatrician, pediatric neurologist, dietitian, and physical therapist when possible.
No specific dietary or other metabolic treatment is available.
Thorough developmental assessment is indicated for all children who exhibit cognitive difficulties in order to determine strengths and weaknesses and to tailor special education services. Early intervention may include physical therapy, occupational therapy, and/or speech therapy.
Treatment of the neurologic manifestations is per current clinical practice based on the findings. To date no specific recommendations regarding the use of antiepileptic drugs are available.
Excessive drooling can be reduced with botulinum toxin injection in the salivary glands, extirpation of saliva glands, and/or re-routing of glandular ducts [SB Wortmann, personal communication].
Granulocyte-colony stimulating factor (G-CSF) administered subcutaneously can be used to increase neutrophil counts to help reduce the frequency of infections, especially in individuals with the mild or moderate phenotype (see Clinical Description) [SB Wortmann, personal communication].
Note: Immunizations are not contraindicated and all children should be immunized as per national standards.
Surveillance
Neurologic, ophthalmologic, immunologic/hematologic, and orthopedic evaluations are based on individual findings as needed.
Agents/Circumstances to Avoid
Drugs potentially toxic to mitochondria (including chloramphenicol, aminoglycosides, linezolide, valproic acid, and nucleoside reverse transcriptase inhibitors) should be avoided.
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.