Clinical Guidance

No genotype-phenotype correlations have been reported. Nonetheless, the following observations about PN responsiveness may be helpful in guiding clinical management. See for details.

• Seizures in individuals homozygous for the variant may respond to treatment with PN .

• The seizures of four of the seven individuals reported to be homozygous or compound heterozygous for the variant responded to treatment with PN .

• The majority of individuals who are homozygous for the variant , which may be present alongside other homozygous or compound heterozygous PNPO pathogenic variants (i.e., have a total of two or three pathogenic variants), have late-onset seizures that responded to treatment with PN . See also , PNPO-specific laboratory technical considerations.

Source: GeneReviews — "PNPO Deficiency"

Penetrance

Not all individuals homozygous for the variant develop seizures .

Source: GeneReviews — "PNPO Deficiency"

Diagnostic Criteria

No consensus clinical diagnostic criteria for pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency have been published.

Suggestive Findings

PNPO deficiency should be suspected in individuals with the following suggestive clinical phenotypes, positive response to a standardized vitamin B6 trial, supportive laboratory findings, and family history.

Clinical Findings

Classic PNPO deficiency (defined as neonatal onset) in premature infants and neonates

Source: GeneReviews — "PNPO Deficiency"

Differential Diagnosis

PNPO deficiency must be distinguished from ALDH7A1 deficiency and PLPHP deficiency (also referred to as PLPBP deficiency), as well as other disorders associated with pyridoxine (PN)- and pyridoxal 5'-phosphate (PLP)-responsive seizures . Table 3. Selected Disorders of Interest in the Differential Diagnosis of PNPO Deficiency

Management Guidelines

No clinical practice guidelines for pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency have been published; however, these are currently being formulated by an international PNPO consortium [Author, personal observation].

Evaluations Following Initial Diagnosis

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

For classic and late-onset PNPO deficiency

• Neurologic examination to evaluate eye movement and muscle tone (for hypotonia or rigidity), and to describe seizure semiology

• EEG including sleep and wake cycles (preferably with a recording time of two hours) beginning at the time of seizure onset

• Physical examination including measurement of weight, length, and head circumferenceand evaluation of liver involvement by determination of transaminases, liver function tests, and abdominal ultrasound

• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of PNPO deficiency in order to facilitate medical and personal decision making

For late-onset PNPO deficiency

• Developmental/educational assessment using age-appropriate standardized testing

• Brain MRI in individuals with abnormal development

Treatment of Manifestations

Targeted Therapy

Source: GeneReviews — "PNPO Deficiency"

Clinical Guidance

Several anti-seizure medications (such as carbamazepine, valproate, phenytoin, and phenobarbital) can cause a low plasma concentration of PLP .

Source: GeneReviews — "PNPO Deficiency"

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.

Source: GeneReviews — "PNPO Deficiency"

Surveillance Guidelines

Table 4. Recommended Surveillance for Individuals with PNPO Deficiency

Source: GeneReviews — "PNPO Deficiency"