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.
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