Clinical Guidance

No genotype-phenotype correlations have been identified. The common c.1279GC; p.(Glu427Gln) pathogenic variant in exon 14 accounts for approximately 33% of pathogenic variants . Homozygous p.(Glu427Gln) variants have been observed in both neonatal- and late-onset PDE-ALDH7A1 . Pathogenic missense variants that result in residual enzyme activity may be associated with a more favorable developmental phenotype .

Source: GeneReviews — "Pyridoxine-Dependent Epilepsy – ALDH7A1"

Diagnostic Criteria

Suggestive Findings

Pyridoxine-dependent epilepsy – ALDH7A1 (PDE-ALDH7A1) should be suspected in individuals with the following clinical findings, response to intravenous (IV) or oral (PO) administration of pyridoxine, laboratory findings, and family history.

Suggestive clinical features

Source: GeneReviews — "Pyridoxine-Dependent Epilepsy – ALDH7A1"

Differential Diagnosis

Pyridoxine-dependent epilepsy – ALDH7A1 (PDE-ALDH7A1) must be distinguished from PNPO deficiency and PLPBP deficiency (also referred to as PLPHP deficiency), as well as other disorders associated with pyridoxine (PN)- and pyridoxal 5'-phosphate (PLP)-responsive seizures . Table 2. Selected Disorders of Interest in the Differential Diagnosis of Pyridoxine-Dependent Epilepsy – ALDH7A1

Management Guidelines

Clinical practice guidelines for pyridoxine-dependent epilepsy – ALDH7A1 (PDE-ALDH7A1) have been published .

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PDE-ALDH7A1, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Neurologic examination to evaluate cranial nerve function, muscle strength, tone (for hypotonia or rigidity), and symmetry, and to describe seizure semiology

• EEG including sleep and wake cycles

• As congenital brain developmental abnormalities may occur in PDE-ALDH7A1, brain MRI when clinically indicated (e.g., macrocephaly, incomplete control of seizures to pyridoxine)

• Developmental assessment including motor, adaptive, cognitive, and speech-language evaluation

• Evaluation for early intervention programs/ special education

• 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 PDE-ALDH7A1 in order to facilitate medical and personal decision making

Treatment of Manifestations

Targeted Therapies

Source: GeneReviews — "Pyridoxine-Dependent Epilepsy – ALDH7A1"

Clinical Guidance

Avoid overuse of pyridoxine (see Targeted Therapies, , Side effects).

Source: GeneReviews — "Pyridoxine-Dependent Epilepsy – ALDH7A1"

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.

Source: GeneReviews — "Pyridoxine-Dependent Epilepsy – ALDH7A1"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended:

• Regular assessment by treating neurologist for:

• Control of epilepsy via targeted therapy with pyridoxine, and need for concomitant use of ASM

• Development of clinical signs of a sensory neuropathy including regular assessments of joint-position sense, ankle jerks, gait, and station

• Assessment for developmental progress and educational needs at each visit

• If lysine reduction therapies are used, regular follow up by a biochemical geneticist and/or medical dietician

Source: GeneReviews — "Pyridoxine-Dependent Epilepsy – ALDH7A1"