Acta Neurol Belg (2016) 116:359–362 DOI 10.1007/s13760-015-0533-x

LETTER TO THE EDITOR

Epilepsy in Kostmann syndrome: report of a case and review of the literature A. Bartocci2 • D. Laino1 • G. Di Cara1 • A. Verrotti1

Received: 8 June 2015 / Accepted: 13 August 2015 / Published online: 29 August 2015 Ó Belgian Neurological Society 2015

Introduction

Case report

Severe congenital neutropenia, also defined as Kostmann syndrome, is a rare primary immunodeficiency, with an estimated frequency of 1–2 cases per 1,000,000 population [1], characterized by the lack of mature neutrophils and frequent bacterial infections in affected patients [2]. Affected patients present myeloid hypoplasia with arrest of myelopoiesis at the promyelocyte/myelocyte stage [1]. More recent studies have identified several mutations in the gene encoding the anti-apoptotic HCLS-1-associated protein X1 (HAX1) in subjects with the autosomal recessive form of the syndrome [2]. HAX1 is a ubiquitously expressed mitochondrial protein with an important role in the stabilization of the mitochondrial membrane potential, and its deficiency causes increased myeloid cell apoptosis [2]. Some patients with Kostmann syndrome present neurological symptoms, including cognitive impairment, severe neurodegeneration and epilepsy [3]. In literature, few cases of epilepsy in Kostmann syndrome have been reported, and clinical and EEG characteristics of these patients have been often poorly defined [4]. We report here the case of a child affected by this syndrome and carrier of HAX1 deficiency who developed mental delay and epilepsy; we reviewed all cases reported in literature to better define the peculiar aspects of the seizures in this syndrome.

The child was born from non-consanguineous parents; the perinatal and personal history was normal. The family history of immunodeficiency and epilepsy was negative. Since the first year of life, he presented recurrent upper respiratory infections and cutaneous perianal abscesses. Such symptoms led to a suspicion of Kostmann syndrome, which was diagnosed at 7.2 years of age with the identification of the Arg86X mutation, affecting both transcript variants of the HAX1 gene. Sequence analysis of his parents and sister demonstrated the same heterozygous mutation. After the diagnosis, as the evaluation of G-CSF receptor did not show any mutation, a therapy with PEGFilgastrim, a PEGylated form of the recombinant human G-CSF analog filgastrim, was started, with an 8-day treatment schedule. Since the beginning of therapy, his neutrophil levels became acceptable, with values within the lower range of normality. At the age of 10.1 years, he presented a brief (3–4 s) right hemiclonic seizure followed by GTCS, interrupted after 2 min with the administration of intrarectal diazepam. The following day, he presented another seizure with similar characteristics. Interictal and critical infraclinical awake EEG (Figs. 1, 2) showed fronto-temporal spikes with diffuse bilateral subcontinuous spikes and waves discharges; 3-T brain MRI was normal. The main secondary causes of epileptic seizures, such as infections and metabolic diseases, were excluded, with normal C-reactive protein, ESR, blood glucose, lactate, ammonium and electrolytes, normal liver and kidney function, and negative blood culture. No echocardiographic abnormality was found. Psychological and psychometric evaluation (Wechsler II scale) showed subnormal intellectual ability (total IQ: 75) and reduced attention span. He started therapy with valproic acid with persistence of

& A. Bartocci [email protected] 1

Department of Pediatrics, University of Perugia, Perugia, Italy

2

Department of Neurophysiopathology, Hospital ‘‘Santa Maria della Misericordia’’, Perugia, Italy

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Fig. 1 Diffuse spikes and waves and high voltage show waves continued without showing any clinical manifestations

monthly seizures, despite the gradual increase in the dosage of the drug (maximum dose 35 mg/kg/daily) and measured blood levels of the latter in the normal range (85 mg/L; range 50–100). During an awake EEG, he presented an episode of GTCS, interrupted after 15 min with the administration of intravenous diazepam. Therefore, valproic acid was discontinued and therapy with topiramate was started (initial dosage 0.6 mg/kg/daily) with a subsequent complete disappearance of seizures. At the last follow-up evaluation, performed after 15 months from the onset of epilepsy, he continued to be seizure free with topiramate monotherapy (1.8 mg/kg/daily) and EEG normalized. The normalization of EEG and the good response to antiepileptic therapy with topiramate did not substantially change the cognitive performance of the child; these findings support the hypothesis that seizures and EEG abnormalities were not the causes of the mild mental retardation presented by the patient.

Discussion Our report describes a patient with Kostmann syndrome and epilepsy. Considering the presence of a clear epileptogenic focus in the interictal EEG, our child presented

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focal seizures with secondary generalization. The association between Kostmann syndrome and epilepsy has been previously reported, but with incomplete data, in a few reports (see Table 1) [1]. However, none of these papers have focused on the seizures type, EEG abnormalities and response to antiepileptic therapy. In our patient, the EEG recording suggested the presence of a focal seizure with secondary generalization; such findings, apparently unusual in the EEG evaluation of children with idiopathic epilepsy, could be possibly considered as a typical comorbidity of Kostmann syndrome. In fact, our patient did not present other predisposing factors for epilepsy, and familiar history for epilepsy was negative. Other cases described in literature did not present familiarity for epilepsy; the only interesting familiar finding is in a study that described Kostmann syndrome and epilepsy affecting both brothers who were born from consanguineous parents [4]. When reported in other studies, interictal EEG recordings showed generalized or, sometimes, focal paroxistic activity, with onset, in particular, from occipital regions. Valproic acid was the most used drug [1–5] with a good response, except for one patient, who responded to clonazepam [5]. In contrast, our patient did not present a good response to valproic acid, while topiramate led to a rapid resolution of seizures and of EEG abnormalities. Our case

Acta Neurol Belg (2016) 116:359–362

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Fig. 2 Intercritical focal EEG: right fronto-temporal spikes and waves

Table 1 Clinical and electroencephalographic characteristics of epilepsy in Kostmann syndrome Authors

No. of pts

Onset age

Seizure type

EEG

Imaging studies

Treatment

Prognosis

Rezaei et al.

1

9 months

Myoclonic seizures

Multifocal abnormalities

Normal

LTG

Good

Matsubara et al.

1

4 years

Atypical absence

Generalized abnormalities

Normal

Germeshausen et al.

2

N.A.

N.A.

Pathologic

Normal

N.A.

N.A.

Carlsson et al.

3

11–14 years

GTCS

Generalized and focal abnormalities

N.A.

VPA

Good

VPA

Poor with VPA, good with CZP

PB VPA CLB

Partial control of seizures

ESM

Focal Ul-Haque et al.

1

4 years

Atonic seizures

Generalized abnormalities

Normal

Boztug et al.

1

3 years

GTCS

Focal abnormalities

Pathologic

VPA

Good

Our case

1

10.1 years

Hemiclonic seizures with GTCS

Focal abnormalities

Normal

VPA

Poor with VPA, good with TPM

CZP

TPM

GTCS generalized tonic–clonic seizures, LTG lamotrigine, PB phenobarbital, VPA valproic acid, CLB clobazam, ESM ethosuximide, CZP clonazepam, TPM topiramate, N.A. not available

provides further evidence of the presence of focal epilepsy with secondary generalization; despite the absence of sufficient data to confirm this association, we can suggest that epilepsy should be considered as a comorbidity of

Kostmann syndrome. The real link between this disease and epilepsy is still unclear and under debate, although our description and the analysis of the literature suggest that such association may not be coincidental. Epilepsy etiology

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remains elusive; epilepsy could be related to the immunological abnormalities present in Kostmann syndrome. In fact, in recent years, there is an increasing knowledge on the possible association between epilepsy and immunological disorders [6–8]. It is possible that, in the presence of mitochondrial impairment with subsequent decreased energy production, increased oxidative stress and release of cellular apoptosis factors, the central nervous system could be impaired, because of its great dependence on oxidative metabolism. Thus, epilepsy could be, in some patients, the first clinical feature of an underlying mitochondrial disease, although this hypothesis cannot be confirmed by our patient, who showed no cardiac and blood abnormality, suggesting a mitochondrial involvement. It is important to remember that HAX1 is an important mitochondrial protein, involved in the stabilization of the mitochondrial membrane potential; therefore, the mutation of the HAX1 gene can contribute to the onset of seizures in these patients. The HAX1 gene has two different splice variants which represent isoforms A and B; mutations of isoform A (W44X, Glu59X, Glu60fs) do not cause neurological symptoms, while mutations of both isoforms A and B (Arg86X, Gln123fs, Val144fs, Gln190X) are related to extra neurological disorders, including developmental and mental delay, and seizures. The Arg86X homozygous mutation found in both isoforms A and B of our patient, in accord with previous studies, confirms that such mutation can be related to the onset of epilepsy [4, 5]. In conclusion, epilepsy in Kostmann syndrome is an important feature with a fair prognosis and a generally good response to antiepileptic therapy. Further studies should focus on the EEG characteristics and seizures type to verify if the pattern of a focal primary focal activity correlates to a poor response to valproic acid or if such EEG findings are typical of patients with Kostmann syndrome and epilepsy.

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Acta Neurol Belg (2016) 116:359–362 Compliance with ethical standards Conflict of interest interest.

The authors declare that there is no conflict of

Ethical approval All procedures performed in the study were in accordance with the ethical standards of the institutional committee and with the Helsinki declaration. Informed consent of the patient.

Informed consent was obtained from the parents

References 1. Rezaei N, Moin M, Pourpak Z et al (2007) The clinical, immunohematological, and molecular study of Iranian patients with severe congenital neutropenia. J Clin Immunol 27:525–533 2. Matsubara K, Imai K, Okada S et al (2007) Severe developmental delay and epilepsy in a Japanese patient with severe congenital neutropenia due to HAX1 deficiency. Haematologica 92:e123– e125 3. Germeshausen M, Grudzien M, Zeidler C et al (2008) Novel HAX1 mutations in patients with severe congenital neutropenia reveal isoform-dependent genotype–phenotype associations. Blood 15(111):4954–4957 4. Carlsson G, Van’t Hooft I, Melin M et al (2008) Central nervous system involvement in severe congenital neutropenia: neurological and neuropsychological abnormalities associated with specific HAX1 mutations. J Intern Med 264:388–400 5. Faiyaz-Ul-Haque M, Al-Jefri A, Al-Dayel F et al (2010) A novel HAX1 gene mutation in severe congenital neutropenia (SCN) associated with neurological manifestations. Eur J Pediatr 169:661–666 6. Vezzani A (2014) Epilepsy and inflammation in the brain: overview and pathophysiology. Epilepsy Curr 14:3–7 7. Benros ME, Sørensen HJ, Nielsen PR et al (2015) The association between infections and general cognitive ability in young men—a Nationwide Study. PLoS One 13:10 8. van Engelen BG, Renier WO, Weemaes CM et al (1994) Immunoglobulin treatment in epilepsy, a review of the literature. Epilepsy Res 19:181–190

Epilepsy in Kostmann syndrome: report of a case and review of the literature.

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