Pyridoxine-dependent epilepsy

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: ALDH7A1 (HGNC:877)
• Literature Search: 12/17/2018
• Curation Status: Released (1.1.4)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
ALDH7A1	pyridoxine-dependent epilepsy caused by ALDH7A1 mutant (0020741)	266100	Strong Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion computed according to the rubric.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Seizures / Pyridoxine therapy	2	3C	3B	3	11CB

Severity of Outcome

Prevalence of the Genetic Condition

Population prevalence of pyridoxine-dependent epilepsy (PDE) has been estimated in various populations to be 1:20,000-783,000.

Clinical Features (Signs / symptoms)

PDE is a rare neurometabolic disease. Clinical findings include intractable seizures that are not controlled with antiepileptic drugs (AEDs). Multiple types of seizures have been reported in patients with PDE, even in the individual patient. Most commonly, prolonged seizures and recurrent episodes of status epilepticus are observed; recurrent self-limited events including partial seizures, generalized seizures, atonic seizures, myoclonic events, infantile spasms, and electrographic seizures without clinical correlates also occur. Additional symptoms alongside seizures include irritability, crying, poor feeding, gastrointestinal symptoms (emesis, abdominal distention), sleeplessness, facial grimacing, and abnormal eye movements. Neonatal lactic acidosis, hypoglycemia, profound electrolyte disturbances, hypothyroidism, and diabetes insipidus have been reported in patients with PDE. Most patients, despite seizure control, have developmental delay and intellectual disability, although patients with normal intellectual function have been reported. Intellectual disability can range from mild to severe (particularly affecting expressive language domain). Imaging abnormalities often include thinning of the corpus callosum (particularly of the isthmus) and can include mega cisterna magna, enlarged ventricles and diffuse cerebral hemispheric gray and white matter atrophy. Periventricular dysmyelination is common in older children.

Natural History (Important subgroups & survival / recovery)

The clinical spectrum of PDE includes a “classic” presentation (neonatal or infancy onset) and an “atypical” presentation (onset varies from late infancy up to 3 years of age). The atypical presentation of PDE may account for 1/3 of cases and can include autism, initial response to common AEDs (especially phenobarbital) but later seizures that become intractable, response to extremely low doses of pyridoxine, initial lack of response to pyridoxine but then a response several months later, and prolonged seizure-free intervals after the discontinuation of pyridoxine treatment. Seizures in some individuals with ALDH7A1 pathogenic variants are incompletely controlled with pyridoxine and concurrent treatment with one or more AEDs is required; significant intellectual disability is present in these individuals. Prognosis is variable and depends, in part, on genotype, associated abnormalities in brain development, and response to pyridoxine treatment.

Likelihood of Outcome

Prevalence of Genetic Variants

The prevalence of pathogenic ALDH7A1 variants is unknown but should be similar to carrier frequencies required to yield PDE prevalence cited in this report, as ALDH7A1 pathogenic variants have been identified as the major underlying genetic cause of PDE.

Penetrance (Includes any high-risk racial or ethnic subgroups)

No penetrance data from unselected populations was available.

Tier Not provided

All individuals with PDE have intractable seizures that respond both clinically and electrographically to large daily supplements of pyridoxine.

Tier 4

75%-80% of patients with PDE have developmental delay and/or intellectual disability (IQ < 70), despite pyridoxine treatment.

Tier 3

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Information on relative risk was not available.

Expressivity

There may be substantial inter-patient differences in the required effective dose related to the underlying ALDH7A1 pathogenic variant, or to other genetic causes, or to environmental influences such as the patient’s lysine intake. Seizure types are variable even in the individual patient. Patients treated as early as in the neonatal period may have developmental delay and intellectual disability, whereas other patients with prolonged status epilepticus and later diagnosis may have a normal IQ.

Tier 3

No firm genotype-phenotype correlations are known. Pathogenic missense variants that result in residual enzyme activity may be associated with a more favorable developmental phenotype.

Tier 3

Intervention Effectiveness

Patient Management

To establish the extent of disease and needs in an individual diagnosed with PDE, the following are appropriate:

-Developmental assessment

-Consultation with a clinical geneticist and/or genetic counselor.

Tier 4

The standard treatment for PDE includes lifelong supplementation of pyridoxine in pharmacological doses. This recommendation is based on data from a registry cohort of 63 individuals receiving pyridoxine monotherapy. Of these, 47 (75%) were seizure-free except in times of illness or non-compliance on monotherapy. An additional 8 (13%) were controlled on pyridoxine plus additional anticonvulsants. The remainder (13%) continued to have seizures despite combination therapy with pyridoxine and multiple anticonvulsants.

Tier 2

For acute care (to interrupt seizures), pyridoxine is given intravenously or orally/enterally. A single dose often results in cessation of seizures within minutes. First administration may result in respiratory arrest, so treatment should be performed with the support of respiratory management.

Tier 2

Surveillance

Brain MRI/MRS should be performed as needed to monitor cerebral myelination and metabolism.

Tier 2

Regular assessments of intellectual function should be offered.

Tier 4

Circumstances to Avoid

No recommendations related to circumstances to avoid were identified.

Nature of Intervention

Nature of Intervention

Pyridoxine treatment for PDE is administered daily and is life-long. Compliance with pyridoxine supplementation is critical, as status epilepticus may develop within days of discontinuation of pyridoxine (time interval between 1 and 51 days have been reported). Initial treatments may be given intravenously, but as intravenous pyridoxine can cause apnea, IV administration should not be performed outside an ICU setting or without readiness to intubate. However, staff has to be aware that apnea requiring intubation has even been observed in single patients after a first oral administration of pyridoxine. Long-term, treatments can be given orally.

Context: Pediatric

Affected individuals should have regular screening for peripheral neuropathy as an adverse effect of pyridoxine treatment, including sensory neuropathy, via detailed clinical neurological exam. Nerve conduction studies can be performed regularly or upon clinical evidence of neuropathy, in particular if high doses of pyridoxine are needed.

Context: Pediatric

Overuse of pyridoxine should be avoided, as it can cause a reversible sensory neuropathy (ganglionopathy) in individuals with PDE. This recommendation is primarily based on healthy individuals taking overdosages of pyridoxine, but case reports exist of pyridoxine-caused neuropathy in individuals with PDE.

Context: Pediatric

Chance to Escape Clinical Detection

There are no EEG abnormalities that are pathognomonic for this condition, and dramatic presentations such as status epilepticus (that is unresponsive to AEDs) are common. Additionally, depending on symptoms present at birth, it is possible for the condition to be misdiagnosed as drug withdrawal syndrome or neonatal hypoxic ischemic encephalopathy. A preliminary diagnosis of hypoxic ischemic encephalopathy may prevent further diagnostic workup of neonatal seizures and responsiveness to pyridoxine may not be tested at all.

Context: Pediatric

Tier 3

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			ALDH7A1			266100	0020741

References List

EPILEPSY, PYRIDOXINE-DEPENDENT; EPD. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 266100, (2018) World Wide Web URL: http://omim.org/

Pyridoxine-dependent epilepsy. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=3006

SM Gospe. Pyridoxine-Dependent Epilepsy. (2001) [Updated Apr 13 2017]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1486/

Stockler S, Plecko B, Gospe SM Jr, Coulter-Mackie M, Connolly M, van Karnebeek C, Mercimek-Mahmutoglu S, Hartmann H, Scharer G, Struijs E, Tein I, Jakobs C, Clayton P, Van Hove JL. (2011) Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Molecular genetics and metabolism. 104(1-2):48-60.

van Karnebeek CD, Stockler-Ipsiroglu S, Jaggumantri S, Assmann B, Baxter P, Buhas D, Bok LA, Cheng B, Coughlin CR 2nd, Das AM, Giezen A, Al-Hertani W, Ho G, Meyer U, Mills P, Plecko B, Struys E, Ueda K, Albersen M, Verhoeven N, Gospe SM Jr, Gallagher RC, Van Hove JK, Hartmann H. (2014) Lysine-Restricted Diet as Adjunct Therapy for Pyridoxine-Dependent Epilepsy: The PDE Consortium Consensus Recommendations. JIMD reports. 15(2192-8304):1-11.