PIGA mutations cause early-onset epileptic encephalopathies and distinctive features.

OBJECTIVE: To investigate the clinical spectrum caused by mutations in PIGA at Xp22.2, which is involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor, among patients with early-onset epileptic encephalopathies (EOEEs). METHODS: Whole-exome sequencing was performed as a comprehensive genetic analysis for a cohort of 172 patients with EOEEs including early myoclonic encephalopathy, Ohtahara syndrome, and West syndrome, and PIGA mutations were carefully investigated. RESULTS: We identified 4 PIGA mutations in probands showing early myoclonic encephalopathy, West syndrome, or unclassified EOEE. Flow cytometry of blood granulocytes from patients demonstrated reduced expression of GPI-anchored proteins. Expression of GPI-anchored proteins in PIGA-deficient JY5 cells was only partially or hardly restored by transient expression of PIGA mutants with a weak TATA box promoter, indicating a variable loss of PIGA activity. The phenotypic consequences of PIGA mutations can be classified into 2 types, severe and less severe, which correlate with the degree of PIGA activity reduction caused by the mutations. Severe forms involved myoclonus and asymmetrical suppression bursts on EEG, multiple anomalies with a dysmorphic face, and delayed myelination with restricted diffusion patterns in specific areas. The less severe form presented with intellectual disability and treatable seizures without facial dysmorphism. CONCLUSIONS: Our study confirmed that PIGA mutations are one genetic cause of EOEE, suggesting that GPI-anchor deficiencies may be an underlying cause of EOEE.

A girl with Cardio-facio-cutaneous syndrome complicated with status epilepticus and acute encephalopathy.

We report a six-year-old girl with Cardio-facio-cutaneous (CFC) syndrome who developed acute encephalopathy after the recurrence of status epilepticus. While epileptic encephalopathy and severe epilepsy have been mentioned as frequent complications of the CFC syndrome, no previous reports have shown a case of the CFC syndrome complicated with acute encephalopathy. Here we discuss the possibility for the linkage between the development of acute encephalopathy and CFC syndrome which is generally susceptible to seizures or epilepsy.

Schinzel-Giedion syndrome: a further cause of early myoclonic encephalopathy and vacuolating myelinopathy.

Here, we report a male child with Schinzel-Giedion syndrome associated with intramyelinic edema detected on brain magnetic resonance imaging (MRI) and persistent suppression-burst pattern on electroencephalography (EEG) with erratic myoclonus of the extremities and face. Similar to nonketotic hyperglycinemia, Schinzel-Giedion syndrome may be recognized as another causative genetic disease of early myoclonic encephalopathy and vacuolating myelinopathy.

Central tegmental tract lesion in a girl with holoprosencephaly presenting with West syndrome.

We described a 16-month-old female patient who developed West syndrome at 3 months of age. MRI revealed a holoprosencephaly with incomplete fusion of the cerebrum, associated with central tegmental tract (CTT) lesions. At 1 year of age, the CTT lesion was still present on T2-weighted MRI. The CTT represents an important projection pathway of the extrapyramidal tract and the CTT lesions have rarely been reported using MRI in patients with neonatal hypoxic-ischemic encephalopathy and several inborn errors of metabolism. Although the exact mechanism remains obscure, we suggest that disturbances in midbrain fibers that connect to the basal ganglia, may have contributed to the etiology of West syndrome in this patient.

[Case of west syndrome associated with transient marked sinus dysfunction during ACTH therapy].

An 11-month-old boy with multiple congenital anomalies developed West syndrome and ACTH therapy was started. Marked bradycardia during sleep was observed after the 16th day of ACTH therapy. Echocardiography revealed both intraventricular septum and left ventricular free wall thickening with preservation of biventricular function. Both the patient's marked sinus dysfunction and his cardiac hypertrophy were suspected to be related to the ACTH therapy. Sinus function gradually improved after ACTH therapy was withdrawn and treatment with oral beta-agonist was started. We believe that the patient's sinus dysfunction and cardiac hypertrophy were caused by ACTH treatment because of the subacute nature of the onset and the absence of other potentially contributory factors such as infection or respiratory failure. Pediatricians should be aware that cardiac dysfunction could be associated with ACTH therapy for West syndrome.

[A case of non-herpetic acute limbic encephalitis in childhood--comparison with acute encephalitis with refractory repetitive partial seizures (AERRPS)].

A 9-year-old boy was diagnosed as non-herpetic acute limbic encephalitis (NHALE). Four days after the gastrointestinal infection, he developed a generalized seizure accompanied with delirium and psychiatric change, which evolved into intractable seizures. These seizures were complex partial seizures or generalized tonic clonic seizures, and were highly resistant to many anticonvulsants. Magnetic resonance imaging of the brain demonstrated reversible symmetrical high-intensity lesions in the claustra on the diffusion-weighted image. Laboratory findings did not suggest herpes simplex virus infection. Further, the clinical findings were consistent with those in acute encephalitis with refractory repetitive partial seizures (AERRPS). We assume that a part of AERRPS belongs to the category of parainfectious limbic encephalitis with repetitive seizures.

Neonatal-onset brainstem reticular reflex myoclonus following a prenatal brain insult: generalized myoclonic jerk and a brainstem lesion.

Brainstem reticular reflex myoclonus (BRRM) is characterized by sudden, generalized, shock-like movements that can be elicited by sensory stimulation. We present a boy, born after 35 weeks gestation, who was diagnosed with neonatal-onset BRRM. Within 1 hr of birth, the patient showed spasticity and generalized clonic movements of all limbs elicited with tactile stimulation anywhere on the body. Surface electromyography showed co-contraction of agonistic and antagonistic muscles, revealing that his generalized clonic movements were tremulous myoclonus in nature. Brain magnetic resonance imaging (MRI) at 21 hrs after birth disclosed high-intensity lesions in the Rolandic area, thalamus, basal ganglia, and brainstem, including the dorsal pons and medulla, the center of BRRM, in T1-weighted images. Follow-up MRI at 1 month revealed dramatic improvement in the pontine lesion. The patient showed gradual remission of the characteristic movements, which disappeared at 1 year of age, but the patient died unexpectedly at 1 year and 3 months. In conclusion, neonatal BRRM arises as a result of severe brainstem injury, and the associated lesions may only be seen temporarily on MRI taken soon after birth.