Clinical characteristics.

CLPB (caseinolytic peptidase B) deficiency is characterized by neurologic involvement and neutropenia, which can range from severe to mild. In severe CLPB deficiency, death usually occurs at a few months of age due to 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. Individuals with moderate CLPB deficiency present with neurologic abnormalities in infancy including hypotonia and feeding problems, and develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability. Neutropenia is variable, but not life threatening. In those with mild CLPB deficiency there is no neurologic involvement, intellect is normal, neutropenia is mild and intermittent, and life expectancy is normal.

Diagnosis/testing.

The diagnosis of CLPB deficiency is established in a proband by identification of biallelic pathogenic variants in CLPB or identification of one of several specific heterozygous CLPB pathogenic variants associated with autosomal dominant CLPB deficiency on molecular genetic testing.

Management.

Treatment of manifestations: Treatment is supportive. A multidisciplinary team including a metabolic physician, pediatric neurologist, dietitian, and physical therapist is recommended. No specific dietary or metabolic treatment is available. Feeding therapy; gastrostomy tube placement for persistent feeding issues; treatment of seizures per neurologist; management of movement disorder per orthopedist, physical medicine and rehabilitation specialist, physical therapist, and occupational therapist; botulinum toxin injection in the salivary glands, extirpation of saliva glands, and/or rerouting of glandular ducts for excessive drooling; developmental support including early intervention (physical therapy, occupational therapy, and/or speech therapy) and special education services; granulocyte-colony stimulating factor to increase neutrophil counts to reduce the frequency of infections, especially in individuals with the mild or moderate phenotype; standard immunizations to prevent infections; treatment of cataracts per ophthalmologist; treatment of endocrine dysfunction per endocrinologist; treatment of renal disease per renal specialist; consider hematopoietic stem cell transplant in those without severe neurologic disease.

Surveillance: At each visit: assess for seizures, changes in tone, and movement disorders; assess growth, feeding, developmental progress, mobility, and family needs; measure white blood cell count with differential. Ophthalmology examination with frequency per ophthalmologist. Annually: TSH to assess thyroid function; assessment of gonadal function in females (beginning at age 10 years).

Agents/circumstances to avoid: Drugs potentially toxic to mitochondria, including chloramphenicol, aminoglycosides, linezolid, valproic acid, and nucleoside reverse transcriptase inhibitors.

Genetic counseling.

CLPB deficiency associated with biallelic CLPB pathogenic variants is inherited in an autosomal recessive manner. CLPB deficiency associated with specific heterozygous CLPB pathogenic variants is inherited in an autosomal dominant manner.

• Autosomal recessive CLPB deficiency. If both parents are known to be heterozygous for a CLPB pathogenic variant associated with autosomal recessive CLPB deficiency, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial CLPB pathogenic variants. Carrier testing for at-risk relatives requires prior identification of the CLPB pathogenic variants in the family.
• Autosomal dominant CLPB deficiency. All individuals reported to date with autosomal dominant CLPB deficiency have the disorder as the result of a de novo CLPB pathogenic variant. Each child of an individual with a heterozygous CLPB pathogenic variant has a 50% chance of inheriting the pathogenic variant.

Once the CLPB pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for CLPB deficiency are possible.

Suggestive Findings

CLPB (caseinolytic peptidase B) deficiency should be suspected in individuals with the following clinical, laboratory, and imaging findings.

Establishing the Diagnosis

The diagnosis of CLPB deficiency is established in a proband with one or more suggestive findings and/or ONE of the following identified on molecular genetic testing (see Table 1):

• Biallelic CLPB pathogenic (or likely pathogenic) variants
• A heterozygous CLPB pathogenic (or likely pathogenic) variant associated with autosomal dominant CLPB deficiency (See Genotype-Phenotype Correlations.)

Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel, single-gene testing) and comprehensive genomic testing (exome sequencing, 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 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).

Clinical Description

The clinical phenotype of CLPB deficiency ranges from severe 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 [Pronicka et al 2017].

To date a total of 32 individuals from 16 families with biallelic CLPB pathogenic variants have been reported in the literature (n=14 [Wortmann et al 2015], n=5 [Pronicka et al 2017], 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.

Autosomal dominant CLPB deficiency has been reported in 16 probands (from 16 families) with severe to mild phenotypes [Wortmann et al 2021, Warren et al 2022].

Genotype-Phenotype Correlations

Individuals with the most severe phenotypes often have pathogenic variants predicted to lead to the complete absence of functional protein.

Autosomal dominant CLPB deficiency has been reported in six individuals with the following pathogenic variants: c.1211A>C (p.Lys404Thr), c.1280C>T (p.Pro427Leu), c.1678G>A (p.Gly560Arg), and c.1681C>T (p.Arg561Trp); phenotype varied from severe to mild. These variants disturb refoldase and to a lesser extent ATPase activity of CLPB in a dominant-negative manner. Urinary excretion of 3-methylglutaconic acid (3-MGA) was elevated in all six individuals assessed [Wortmann et al 2021].

Six different heterozygous CLPB pathogenic variants, c.1163C>A (p.Thr388Lys), c.1488T>A (p.Asn496Lys), c.1669G>A (p.Glu557Lys), c.1681C>G (p.Arg561Gly), c.1682G>A (p.Arg561Gln), and c.1858C>T (p.Arg620Cys), were identified in ten unrelated individuals with congenital neutropenia with or without neurologic features and/or cataracts. Urinary excretion of 3-MGA was not elevated in the five individuals in whom it was assessed. All six pathogenic variants were near the C-terminal ATP-binding domain and were predicted to interact with the ATP-binding pocket [Warren et al 2022].

Prevalence

CLPB deficiency is rare. A total of 32 individuals with autosomal recessive CLPB deficiency have been reported to date (n=14 [Wortmann et al 2015], n=5 [Pronicka et al 2017], 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]), and 16 individuals with autosomal dominant CLPB deficiency have been reported (n=10 [Warren et al 2022], n=6 [Wortmann et al 2021]). 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 (associated with autosomal recessive CLPB deficiency) was determined to be 3.3% ‒ comparable to carrier frequencies of other founder variants in Greenland [Saunders et al 2015].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CLPB deficiency, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

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.

Surveillance

Agents/Circumstances to Avoid

Drugs potentially toxic to mitochondria (including chloramphenicol, aminoglycosides, linezolid, 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.

Mode of Inheritance

CLPB deficiency associated with biallelic CLPB pathogenic variants is inherited in an autosomal recessive manner. CLPB deficiency associated with specific heterozygous CLPB pathogenic variants (see Genotype-Phenotype Correlations) is inherited in an autosomal dominant manner. To date, CLPB pathogenic variants reported in individuals with autosomal dominant CLPB deficiency have not been identified in individuals with autosomal recessive CLPB deficiency or in healthy carriers (e.g., parents and sibs of individuals with autosomal recessive CLPB deficiency).

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of a child with biallelic CLPB pathogenic variants are presumed to be heterozygous for a CLPB pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CLPB pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) of pathogenic variants known to be associated with autosomal recessive CLPB deficiency are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a CLPB pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial CLPB pathogenic variants.
• The clinical manifestations of CLPB deficiency are variable and may differ between sibs who inherit identical biallelic CLPB pathogenic variants.
• Heterozygotes (carriers) of pathogenic variants known to be associated with autosomal recessive CLPB deficiency are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• Unless an affected individual's reproductive partner also has autosomal recessive CLPB deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in CLPB.
• The c.803C>T founder variant has a carrier frequency of 3.3% in the Inuit population of Greenland (see Prevalence).

Other family members. Each sib of a heterozygous parent is at a 50% risk of being heterozygous for a CLPB pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the CLPB pathogenic variants in the family.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• All individuals reported to date with autosomal dominant CLPB deficiency have the disorder as the result of a de novo CLPB pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the CLPB pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with autosomal dominant CLPB deficiency may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• The clinical manifestations of CLPB deficiency are variable and may differ between sibs who inherit a CLPB pathogenic variant associated with autosomal dominant CLPB deficiency.
• If the CLPB pathogenic variant detected in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the CLPB pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be slightly greater than that of the general population because of the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with a heterozygous CLPB pathogenic variant has a 50% chance of inheriting the CLPB pathogenic variant.

Other family members. Given that all probands with autosomal dominant CLPB deficiency reported to date have the disorder as a result of a de novo CLPB pathogenic variant, the risk to other family members is presumed to be low; however, if a parent has the CLPB pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected with CLPB deficiency or are carriers (or are at risk of being carriers) of autosomal recessive CLPB deficiency.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the CLPB pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CLPB deficiency are possible. Note: Because intrafamilial variability is observed in CLPB deficiency, the prenatal finding of one pathogenic variant (in families with autosomal dominant CLPB deficiency) or two pathogenic variants (in families with autosomal recessive CLPB deficiency) cannot be used to predict clinical manifestations or disease course.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

CLPB, a mitochondrial protein of poorly known function in human, is a member of the large AAA (ATPases associated with diverse cellular activities) protein superfamily. Members of this superfamily are involved in various processes, such as DNA replication and repair and protein disaggregation and refolding, and operate as part of dynein motors, as chelatases or proteases [Snider et al 2008]. CLPB has been shown to be involved in protein refolding [Mróz et al 2020].

Mechanism of disease causation. Loss of function

CLPB-specific laboratory technical considerations. The canonic splice isoform of CLPB, NM_030813.5, consists of 17 exons. Three other isoforms (NM_001258392.2, NM_001258393.2, NM_001258394.2) result in a shorter open reading frame. NM_001258394.2 has more exons than NM_030813.5 resulting in a longer transcript; however, the resulting protein is shorter and has a different N terminus because an additional exon in NM_030813.5 (between exons 2 and 3) contains an alternate start codon. Until proven otherwise, molecular genetic testing should include all exons of all isoforms.

Author Notes

Dr SB Wortmann and Prof RA Wevers are interested in patients with elevated urinary excretion of 3-methylglutaconic acid. Combining the clinical, biochemical, and neuroradiologic findings of these patients, they are able to define homogeneous subgroups. Next-generation sequencing is then used to identify the underlying genetic disorders in these subgroups, followed by biochemical investigations to characterize the function of the affected protein.

Author History

Arjan PM de Brouwer, PhD; Radboud University Medical Center (2016-2022)
Ron A Wevers, PhD (2016-present)
Saskia B Wortmann, MD, PhD (2016-present)

Revision History

• 10 March 2022 (sw) Comprehensive update posted live
• 22 November 2016 (bp) Review posted live
• 21 June 2016 (sbw) Original submission

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