Elsevier

Brain and Development

Volume 23, Issue 7, November 2001, Pages 765-769
Brain and Development

Review article
The PEHO syndrome

https://doi.org/10.1016/S0387-7604(01)00283-2Get rights and content

Abstract

The progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome is a pediatric disorder of unknown origin, characterized by a combination of postnatally progressive encephalopathy, hypsarrhythmia, and optic atrophy. The pathological findings are early progressive atrophy of the cerebellum, brainstem, and optic nerves. Nitric acid (NO) has recently been implicated in the mechanisms of seizure activity and neurodegeneration, which are both very active in the PEHO syndrome. However, recent studies have provided evidence that insulin-like growth factor 1 (IGF-1) may prevent the NO-mediated neuronal damage and is essential for the survival of the cerebellar granule cells. These cells will degenerate in the PEHO syndrome. In this study, we set out to test the hypothesis that NO production is activated in the PEHO syndrome and that NO production may be correlated with the reduced production of IGF-1 in the brain. Cerebrospinal fluid IGF-1 was determined with an RIA kit and NO metabolites by the Griess calorimetric method. In patients with the PEHO syndrome, as compared with controls, the levels of IGF-1 were reduced and the levels of nitrite/nitrate were markedly elevated. Defective production of IGF-1 probably reflects the underlying neurodegeneration and the increase in NO production probably reflects the seizure activity and/or neurodegeneration. These are the first biochemical abnormalities found in the PEHO syndrome and their study may lead to a better understanding of this devasting disease.

Introduction

An attempt has been made here to evaluate the role of insulin-like growth factor (IGF)-1 and nitric oxide (NO) in the pathogenesis of the progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome.

Section snippets

What is this syndrome?

The PEHO syndrome is a progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy. It is a severe progressive encephalopathy with onset in early infancy.

The distinct clinical criteria for the PEHO syndrome are the following:

  • 1.

    Infantile, usually neonatal, hypotonia.

  • 2.

    Convulsions; seizure onset at 2–52 weeks of life: myoclonic jerking and infantile spasms and/or hypsarrhythmia.

  • 3.

    Early arrest of mental development; absence of motor milestones (no head support or ability to sit

History

In 1991, Salonen et al.[2] described this syndrome in 14 Finnish patients. In the 1990s, Somer collected 53 patients with suspected PEHO syndrome from Finland but discarded half because they did not fulfill the uniform characteristics for the syndrome. It was she who determined the strict criteria for the delineation of the syndrome. The final clinical series comprised 21 patients. Seven patients were available from the original study by Salonen et al. [2] and 14 additional patients were found

Epilepsy

Seizures were suspected in four out of 10 patients before onset of infantile spasms. In eight out of 10 patients, infantile spasms were noted at ages of 3 to 5 months, but in two out of 10 patients, they appeared at ages of 9 and 10 months, respectively. After the infantile spasms, most patients continued to have daily seizures, resistant to antiepileptic drugs [1].

The initial electroencephalograms (EEGs) were normal in two patients at ages of 3 weeks and 4.5 months, respectively. The EEGs were

What is the cause of this syndrome?

The uniform pathological findings in the cerebellum and optic nerves suggest that the patients all have a similar defect in the same, at present unknown gene. However, no genetic defects have been found. Autosomal recessive inheritance is supported by several factors. Affected male and female sibs in three families showed no difference as regards the severity of the disorder. The mothers of two families were fourth cousins. None of the eight maternal half sibs of PEHO patients of four families

Purpose of the study

The purpose of the study was to see whether the levels of insulin-like growth factor 1 (IGF-1), insulin binding protein 3 (IGFB-3), and nitric oxide (NO) in the cerebrospinal fluid (CSF) of patients with the PEHO syndrome differ (1) from the those of the controls and (2) from those of PEHO-like patients.

IGF-1, IGF-2, and insulin are members of the insulin gene family which stimulate cellular proliferation and differentiation during embryonic and postnatal development. Up to 50% of the neurons

Results

We found that

  • 1.

    The levels of IGF-1 in the patients with PEHO syndrome were significantly lower than in the controls and in the PEHO-like syndrome (Fig. 3a) [22].

  • 2.

    The levels of the NO, metabolites, nitrite, and nitrate were markedly elevated in the patients with PEHO and PEHO-like patients as compared with the controls (Fig. 3b) [23]

.

What do these findings mean?

The defective production of IGF-1 probably reflects the underlying neurodegeneration. The highly elevated levels of NO metabolites suggest that these patients suffer from excessive production of NO in the central nervous system (CNS). The increase in NO production likely reflects the underlying pathophysiology, seizure activity and/or neurodegeneration. We believe that these markers reflect separate mechanisms, both of which are deranged in the PEHO syndrome.

These are the first known

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      Once infantile spasms are ameliorated, other types of seizures including myoclonic, tonic, clonic and absence seizures are initiated. Notably, these types of seizures do not respond to antiepileptic drugs [9]. In addition to mentioned clinical features, some unusual features including precocious puberty [10] and dyschromatosis [7] have been reported that may help clarify the etiology of these disorders.

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    • PEHO syndrome may represent phenotypic expansion at the severe end of the early-onset encephalopathies

      2016, Pediatric Neurology
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      The cardinal features of PEHO syndrome include (1) infantile hypotonia, (2) seizure disorder, (3) profound delay in motor and intellectual development, (4) progressive brain atrophy, and (5) atrophy of the optic disc by the age of 2 years. The aforementioned criteria are considered necessary for a diagnosis of PEHO syndrome and together with supportive findings that may include subtle dysmorphic features, edema of the face and limbs, evidence of dysmyelination on brain magnetic resonance imaging studies and slowing of nerve conduction velocities have been used to identify patients with this condition.2-4 Patients who are lacking neuroradiologic and/or ophthalmologic signs have been referred to as PEHO-like syndrome.

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      2012, European Journal of Medical Genetics
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      Recurrence in affected siblings suggests autosomal recessive inheritance [73,77]. Biochemical abnormalities in the cerebrospinal fluid (CSF) of individuals with PEHO or PEHO-like syndrome include increased nitric oxide metabolites [78], and reduced levels of insulin-like growth factor 1 (IGF-1) [74,79]. It has been suggested that the decrease in IGF-1 levels may not be sufficient to prevent nitric oxide mediated neuronal damage, leading to increased nitric oxide production, neurodegeneration and seizures [74].

    • A case of congenital axonal neuropathy associated with West syndrome

      2011, Brain and Development
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      In the case of our patient, the axonal mitochondria were not abnormal. Clinical manifestation in this case showed some common symptoms with PEHO syndrome, characterized by progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy [9]. However, there are no reports on the cases of PEHO syndrome complicated by early-onset peripheral neuropathy.

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      Aspiration pneumonia is the most frequent cause of death in children with PEHO syndrome [2,12]. Epilepsy generally begins with epileptic spasms that are refractory to antiepileptic drugs [3,20]. Other types of epileptic seizures, such as myoclonic jerks and tonic or absence seizures, were also observed [3,20].

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