High diagnostic rate of trio exome sequencing in consanguineous families with neurogenetic diseases.

Consanguineous marriages have a prevalence rate of 24% in Turkey. These carry an increased risk of autosomal recessive genetic conditions, leading to severe disability or premature death, with a significant health and economic burden. A definitive molecular diagnosis could not be achieved in these children previously, as infrastructures and access to sophisticated diagnostic options were limited. We studied the cause of neurogenetic disease in 246 children from 190 consanguineous families recruited in three Turkish hospitals between 2016 and 2020. All patients underwent deep phenotyping and trio whole exome sequencing, and data were integrated in advanced international bioinformatics platforms. We detected causative variants in 119 known disease genes in 72% of families. Due to overlapping phenotypes 52% of the confirmed genetic diagnoses would have been missed on targeted diagnostic gene panels. Likely pathogenic variants in 27 novel genes in 14% of the families increased the diagnostic yield to 86%. Eighty-two per cent of causative variants (141/172) were homozygous, 11 of which were detected in genes previously only associated with autosomal dominant inheritance. Eight families carried two pathogenic variants in different disease genes. De novo (9.3%), X-linked recessive (5.2%) and compound heterozygous (3.5%) variants were less frequent compared to non-consanguineous populations. This cohort provided a unique opportunity to better understand the genetic characteristics of neurogenetic diseases in a consanguineous population. Contrary to what may be expected, causative variants were often not on the longest run of homozygosity and the diagnostic yield was lower in families with the highest degree of consanguinity, due to the high number of homozygous variants in these patients. Pathway analysis highlighted that protein synthesis/degradation defects and metabolic diseases are the most common pathways underlying paediatric neurogenetic disease. In our cohort 164 families (86%) received a diagnosis, enabling prevention of transmission and targeted treatments in 24 patients (10%). We generated an important body of genomic data with lasting impacts on the health and wellbeing of consanguineous families and economic benefit for the healthcare system in Turkey and elsewhere. We demonstrate that an untargeted next generation sequencing approach is far superior to a more targeted gene panel approach, and can be performed without specialized bioinformatics knowledge by clinicians using established pipelines in populations with high rates of consanguinity.

Shared Biological Pathways and Processes in Patients with Intellectual Disability: A Multicenter Study.

BACKGROUND: Although the underlying genetic causes of intellectual disability (ID) continue to be rapidly identified, the biological pathways and processes that could be targets for a potential molecular therapy are not yet known. This study aimed to identify ID-related shared pathways and processes utilizing enrichment analyses. METHODS: In this multicenter study, causative genes of patients with ID were used as input for Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. RESULTS: Genetic test results of 720 patients from 27 centers were obtained. Patients with chromosomal deletion/duplication, non-ID genes, novel genes, and results with changes in more than one gene were excluded. A total of 558 patients with 341 different causative genes were included in the study. Pathway-based enrichment analysis of the ID-related genes via ClusterProfiler revealed 18 shared pathways, with lysine degradation and nicotine addiction being the most common. The most common of the 25 overrepresented DO terms was ID. The most frequently overrepresented GO biological process, cellular component, and molecular function terms were regulation of membrane potential, ion channel complex, and voltage-gated ion channel activity/voltage-gated channel activity, respectively. CONCLUSION: Lysine degradation, nicotine addiction, and thyroid hormone signaling pathways are well-suited to be research areas for the discovery of new targeted therapies in ID patients.

Identification of mutations in the MYO9A gene in patients with congenital myasthenic syndrome.

Congenital myasthenic syndromes are a group of rare and genetically heterogenous disorders resulting from defects in the structure and function of the neuromuscular junction. Patients with congenital myasthenic syndrome exhibit fatigable muscle weakness with a variety of accompanying phenotypes depending on the protein affected. A cohort of patients with a clinical diagnosis of congenital myasthenic syndrome that lacked a genetic diagnosis underwent whole exome sequencing in order to identify genetic causation. Missense biallelic mutations in the MYO9A gene, encoding an unconventional myosin, were identified in two unrelated families. Depletion of MYO9A in NSC-34 cells revealed a direct effect of MYO9A on neuronal branching and axon guidance. Morpholino-mediated knockdown of the two MYO9A orthologues in zebrafish, myo9aa/ab, demonstrated a requirement for MYO9A in the formation of the neuromuscular junction during development. The morphants displayed shortened and abnormally branched motor axons, lack of movement within the chorion and abnormal swimming in response to tactile stimulation. We therefore conclude that MYO9A deficiency may affect the presynaptic motor axon, manifesting in congenital myasthenic syndrome. These results highlight the involvement of unconventional myosins in motor axon functionality, as well as the need to look outside traditional neuromuscular junction-specific proteins for further congenital myasthenic syndrome candidate genes.

Novel mutations in genes causing hereditary spastic paraplegia and Charcot-Marie-Tooth neuropathy identified by an optimized protocol for homozygosity mapping based on whole-exome sequencing.

PURPOSE: Homozygosity mapping is an effective approach for detecting molecular defects in consanguineous families by delineating stretches of genomic DNA that are identical by descent. Constant developments in next-generation sequencing created possibilities to combine whole-exome sequencing (WES) and homozygosity mapping in a single step. METHODS: Basic optimization of homozygosity mapping parameters was performed in a group of families with autosomal-recessive (AR) mutations for which both single-nucleotide polymorphism (SNP) array and WES data were available. We varied the criteria for SNP extraction and PLINK thresholds to estimate their effect on the accuracy of homozygosity mapping based on WES. RESULTS: Our protocol showed high specificity and sensitivity for homozygosity detection and facilitated the identification of novel mutations in GAN, GBA2, and ZFYVE26 in four families affected by hereditary spastic paraplegia or Charcot-Marie-Tooth disease. Filtering and mapping with optimized parameters was integrated into the HOMWES (homozygosity mapping based on WES analysis) tool in the GenomeComb package for genomic data analysis. CONCLUSION: We present recommendations for detection of homozygous regions based on WES data and a bioinformatics tool for their identification, which can be widely applied for studying AR disorders.Genet Med 18 6, 600-607.

Role and Clinical Significance of Plasma N-Terminal Brain Natriuretic Peptide Measurement in Children with Brain Edema.

OBJECTIVE: Brain natriuretic peptide (BNP) is a potent natriuretic and vasodilator factor. BNP plasma concentrations were found to be elevated in patients with brain edema. The purpose of the present study is to evaluate the relationship between plasma NT-proBNP concentration and the presence of brain edema in patients with intracranial pathology. MATERIALS AND METHODS: The plasma NT-proBNP levels of 50 patients and 25 healthy subjects were measured. The NT-proBNP levels of the patient group were measured during admission and after 7 days of treatment. RESULTS: NT-proBNP plasma concentrations were found to be significantly higher in the patient group with brain edema than in the control group (p < 0.005). There were no significant differences in the NT-proBNP plasma concentrations between patients with intracranial pathology without brain edema and the control group (p > 0.005). NT-proBNP plasma concentrations were found to be significantly higher in patients with brain edema as compared with patients without brain edema before treatment (p < 0.005). CONCLUSION: These results suggest that excessive secretion of plasma NT-proBNP is related to brain edema. Plasma NT-proBNP levels may serve as a marker to guide the early-diagnostic and therapeutic management in children with brain edema. Further studies are required to evaluate the role of BNP in brain edema pathophysiology.

A Multinational Survey on Actual Diagnostics and Treatment of Subacute Sclerosing Panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a chronic infection of the central nervous system caused by the measles virus (MV). Its prevalence remains high in resource poor countries and is likely to increase in the Northern Europe as vaccination rates decrease. Clinical knowledge of this devastating condition, however, is limited. We therefore conducted this multinational survey summarizing experience obtained from more than 500 patients treated by 24 physicians in seven countries. SSPE should be considered in all patients presenting with otherwise unexplained acquired neurological symptoms. In most patients, the diagnosis will be established by the combination of typical clinical symptoms (characteristic repetitive myoclonic jerks), a strong intrathecal synthesis of antibodies to MV and typical electroencephalogram findings (Radermecker complexes). Whereas the therapeutic use of different antiviral (amantadine, ribavirin) and immunomodulatory drugs (isoprinosine, interferons) and of immunoglobulins has been reported repeatedly, optimum application regimen of these drugs has not been established. This is partly due to the absence of common diagnostic and clinical standards focusing on neurological and psychosocial aspects. Carbamazepine, levetiracetam, and clobazam are the drugs most frequently used to control myoclonic jerks. We have established a consensus on essential laboratory and clinical parameters that should facilitate collaborative studies. Those are urgently needed to improve outcome.

Clinical features of nine patients with alternating hemiplegia of childhood.

AIM: To define clinical features of patients with alternating hemiplegia of childhood. METHODS: We retrospectively reviewed the clinical presentation and course of the disease in patients diagnosed between January 2003 and December 2008 at the Pediatric Neurology Department of the Istanbul Medical Faculty. RESULTS: The nine patients had a mean age of 6.6 months (2-15 months) at the onset of symptoms. Paroxysmal eye movements were the early symptom of five patients. All patients had recurrent alternating hemiplegic episodes and relief of symptoms while sleeping. Duration of events varied widely from few minutes to several days and was associated with slowly progressive neurological deterioration. Flunarizine might decrease frequency of events but is not effective to neurological deterioration. Amantadine as an alternative agent is used in add-on therapy, but epileptogenic side effect prevented the evaluation of long-term efficacy. CONCLUSION: Trials on new agents like amantadine are necessary for more effective control of the disease.

Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.

Microtubules help building the cytoskeleton of neurons and other cells. Several components of the gamma-tubulin (γ-tubulin) complex have been previously reported in human neurodevelopmental diseases. We describe two siblings from a consanguineous Turkish family with dysmorphic features, developmental delay, brain malformation, and epilepsy carrying a homozygous mutation (p.Glu311Lys) in TUBGCP2 encoding the γ-tubulin complex 2 (GCP2) protein. This variant is predicted to disrupt the electrostatic interaction of GCP2 with GCP3. In primary fibroblasts carrying the variant, we observed a faint delocalization of γ-tubulin during the cell cycle but normal GCP2 protein levels. Through mass spectrometry, we observed dysregulation of multiple proteins involved in the assembly and organization of the cytoskeleton and the extracellular matrix, controlling cellular adhesion and of proteins crucial for neuronal homeostasis including axon guidance. In summary, our functional and proteomic studies link TUBGCP2 and the γ-tubulin complex to the development of the central nervous system in humans.

Brainstem involvement in subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis (SSPE), which usually develops 2-10 years after measles infection, is a progressive neurologic disorder with an insidious onset. The neurologic dysfunctions associated with SSPE include generalized myoclonic jerks and seizure activity, and progression of the disease usually results in coma and death within one to two years after onset. Most of the cerebral lesions in SSPE are observed in the periventricular and subcortical white matter. Brainstem involvement in SSPE is very rare. In this paper, we report two cases with brainstem involvement in SSPE that was accompanied by other intracranial lesions with magnetic resonance imaging (MRI). These two patients died in a short time. Thus, brainstem involvement should be considered in patients with SSPE.

A variety of abnormal movements in 13 cases with nutritional cobalamin deficiency in infants.

HYPOTHESIS: Abnormal movements such as tremor, myoclonus, and choreoathetosis due to infantile nutritional vitamin B12 (Cbl, cobalamin) deficiency or after Cbl injection have been recognized for many years. However, nutritional Cbl deficiency may be more common than recognized and a variety of the abnormal movements may be beyond our estimates. OBJECTIVE: To define the relationship between a large variety of abnormal movements in infants and vitamin B12 deficiency even if serum vitamin B12 levels and/or examination are normal. MATERIALS AND METHODS: This study analyzed a variety of abnormal movements such as involuntary eye movements, limb and body contractions, and gasping as well as clinical, metabolic, radiologic, and treatment results in 13 infants with nutritional Cbl deficiency. This is a retrospective study based on observation and experience. RESULTS: This study included 13 infants (11 boys and 2 girls) with a large spectrum of abnormal movements, the mean age at admission was 8.3 months with a range of 3-22 months. All patients were breastfeeding. In seven cases and their mothers serum vitamin B12 levels were below 200 pg/ml. About one-third of cases serum vitamin B12 levels were over 200 pg/ml. Clinically, mild hypotonia was present in 5 cases, inadequate social interactions in 2 cases, and sensorineural hearing loss in one case. Brain MRI showed frontotemporal enlarged subarachnoid spaces and thinning of the corpus callosum in two cases. EEG examinations were normal in all cases at admission. All cases recovered rapidly within one month with treatment. CONCLUSION: Nutritional Cbl deficiency is a treatable disease that should be considered in the etiology of a variety of movement abnormalities in infants even if serum vitamin B12 values and neurological development are normal.

A rare cause of epileptic encephalopathy: a beta-propeller protein associated neurodegeneration case with a new mutation and literature review.

In this report, detailed clinical features of a female patient and a new mutation that was not previously identified in the WD repeat-containing protein 45 (WDR45) gene are presented in order to contribute to the information in the literature on the phenotype as well as genotype of Beta-Propeller Protein Associated Neurodegeneration. Whole Exome Sequencing (WES) analysis was done since etiology could not be determined. Our case was admitted to the hospital due to epilepsy, growth retardation and autism. Her family history was unremarkable except consanguineous marriage. She had tonic seizures twice at the age of 7 and 12 months and had continual seizures after 16 months. At the time, electroencephalography and brain MRI were performed twice were determined to be normal. Brain MRI Spectroscopy was also found to be normal at 35 months of age. Metabolic screening tests (acyl carnitine profile, urine organic acids, plasma amino acids, a very long chain fatty acid profile, etc.) were also normal. Genetic screening of the epilepsy panel for epileptic encephalopathies was negative. WES analysis revealed heterozygous previously unreported variant in intron 6 of the WDR45 gene, c.344+5G > A. In conclusion; Beta-Propeller Protein Associated Neurodegeneration should be considered as an option in the diagnosis of female patients with clinical findings of epilepsy, growth retardation and autism, with unspecified etiology.

A rare cause of epileptic encephalopathy: a beta-propeller protein associated neurodegeneration case with a new mutation and literature review.

In this report, detailed clinical features of a female patient and a new mutation that was not previously identified in the WD repeat-containing protein 45 (WDR45) gene are presented in order to contribute to the information in the literature on the phenotype as well as genotype of Beta-Propeller Protein Associated Neurodegeneration. Whole Exome Sequencing (WES) analysis was done since etiology could not be determined. Our case was admitted to the hospital due to epilepsy, growth retardation and autism. Her family history was unremarkable except consanguineous marriage. She had tonic seizures twice at the age of 7 and 12 months and had continual seizures after 16 months. At the time, electroencephalography and brain MRI were performed twice were determined to be normal. Brain MRI Spectroscopy was also found to be normal at 35 months of age. Metabolic screening tests (acyl carnitine profile, urine organic acids, plasma amino acids, a very long chain fatty acid profile, etc.) were also normal. Genetic screening of the epilepsy panel for epileptic encephalopathies was negative. WES analysis revealed heterozygous previously unreported variant in intron 6 of the WDR45 gene, c.344+5G > A. In conclusion; Beta-Propeller Protein Associated Neurodegeneration should be considered as an option in the diagnosis of female patients with clinical findings of epilepsy, growth retardation and autism, with unspecified etiology.

Creatine Transporter Deficiency Presenting as Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is the most common disability-causing neurodevelopmental disorder in childhood. Although inborn errors of metabolism (IEM) are rare causes of ASD, they are significant for several reasons, including implications in genetic counseling and determination of prognosis. In this article, we present a 6-year-old boy who presented to us with ASD and was diagnosed with creatine transporter deficiency. Physical and neurologic examination of this patient had not previously raised suspicion of IEM, but twin pregnancy, prematurity, NICU stay due to necrotizing enterocolitis, transient infantile hypotonia, gross-motor delay, breath-holding spells, and a single febrile seizure complicated the history. MRI revealed mild T2-hyperintensity in posterior periventricular white matter. Further evaluation with magnetic resonance spectroscopy, which showed a decreased creatine peak, led to diagnostic investigations for disorders of creatine metabolism, revealing increased urinary creatine:creatinine ratio and a de novo, novel hemizygous frameshift variant in SLC6A8 Clinicians are advised to maintain a high index of suspicion for IEM and to evaluate patients with ASD for syndromic features. Although current guidelines from relevant organizations differ in their recommendations regarding the necessity and the extent of metabolic screening in ASD, there is a growing trend toward screening for treatable IEM. In this case report, we present challenges and pitfalls in the diagnostic journey for creatine transporter deficiency and underline the significance of a thorough history and physical examination in the evaluation of a child with ASD.

COL4A1-related autosomal recessive encephalopathy in 2 Turkish children.

OBJECTIVE: This study presents the neurologic phenotypes of 2 brothers with a novel homozygous COL4A1 mutation that was identified in a large Turkish consanguineous cohort of neurogenetic diseases. METHODS: Whole-exome sequencing and bioinformatic analysis of consanguineous families with children affected by early-onset, neurogenetic disorders was performed using the RD-Connect Genome-Phenome Analysis Platform. We also performed clinical, EEG, and neuroimaging analyses in unaffected siblings and parents. RESULTS: We have identified a homozygous missense mutation in COL4A1 (p.Gly1278Ser, NM_001845.5:c.3832G>T) in 2 siblings affected by small vessel brain disease with periventricular leukoencephalopathy and ocular defects. Presenting symptoms included mild weakness, hemiparetic gait, pyramidal findings, and seizures, whereas their intellectual and behavioral functions were normal. Both parents and 5 of the siblings (3 boys and 2 girls) were heterozygous for the variant. They did not show any clinical or laboratory signs of small vessel disease. CONCLUSIONS: COL4A1 has previously been associated with dominant small vessel disease of the brain and other organs, manifesting with high penetrance in heterozygous mutation carriers. Our findings provide evidence that COL4A1-related encephalopathy can be inherited in an autosomal recessive manner, which is important for counseling, prognosis, and treatment. Genotype-phenotype correlations remain to be established.

Severe neurodevelopmental disease caused by a homozygous TLK2 variant.

A distinct neurodevelopmental phenotype characterised mainly by mild motor and language delay and facial dysmorphism, caused by heterozygous de novo or dominant variants in the TLK2 gene has recently been described. All cases reported carried either truncating variants located throughout the gene, or missense changes principally located at the C-terminal end of the protein mostly resulting in haploinsufficiency of TLK2. Through whole exome sequencing, we identified a homozygous missense variant in TLK2 in a patient showing more severe symptoms than those previously described, including cerebellar vermis hypoplasia and West syndrome. Both parents are heterozygous for the variant and clinically unaffected highlighting that recessive variants in TLK2 can also be disease causing and may act through a different pathomechanism.

Confirmation of TACO1 as a Leigh Syndrome Disease Gene in Two Additional Families.

BACKGROUND: In 2009, we identified TACO1 as a novel mitochondrial disease gene in a single family, however no second family has been described to confirm the role of TACO1 in mitochondrial disease. OBJECTIVE: In this report, we describe two independent consanguineous families carrying pathogenic variants in TACO1, confirming the phenotype. METHODS: Detailed clinical investigations and whole exome sequencing with haplotype analysis have been performed in several members of the two reported families. RESULTS: Clinical phenotype of the patients confirms the originally reported phenotype of a childhood-onset progressive cerebellar and pyramidal syndrome with optic atrophy and learning difficulties. Brain MRI showed periventricular white matter lesions with multiple cystic defects, suggesting leukoencephalopathy in both patients. One patient carried the previously described homozygous TACO1 variant (p.His158ProfsTer8) and haplotype analysis suggested that this variant is a rare founder mutation. The second patient from another family carried a homozygous novel frame shift variant (p.Cys85PhefsTer15). CONCLUSIONS: The identification of two Turkish families with similar characteristic clinical presentation and an additional homozygous nonsense mutation confirms that TACO1 is a human mitochondrial disease gene. Although most patients with this clinical presentation undergo next generation sequencing analysis, screening for selected founder mutations in the Turkish population based on the precise clinical presentation may reduce time and cost of finding the genetic diagnosis even in the era of massively parallel sequencing.

Cerebral vasculitis and obsessive-compulsive disorder following varicella infection in childhood.

Varicella is largely a childhood disease, with more than 90% of cases occurring in children younger than 10 years. The primary infection is characterized by generalized vesicular dermal exanthemas, which are extremely contagious. Secondary bacterial infection and varicella pneumonia, usually seen in the immunocompromised or adult populations, may have high morbidity and mortality. Varicella in childhood is a generally benign and self-limited disorder; however, severe, life-threatening neurological complications may occur. We report a previously healthy eight-year-old boy who presented with acute hemiplegia and obsessive-compulsive disorder secondary to a lesion in lentiform nuclei associated with a history of recent varicella infection. The child was treated with sertraline for obsessive-compulsive disorder symptoms and made a full recovery.

Chest computerized tomography scan findings in 74 children with tuberculous meningitis in southeastern Turkey.

This prospective study was done over seven years from 1996 to 2003 to investigate the chest computed tomography scan findings along with other radiologic examinations that included chest roentgenography and cranial computed tomography in children with tuberculous meningitis (TBM). Chest roentgenography demonstrated abnormal findings in 32 cases (43%) (hilar adenopathy, 32%; miliary pattern, 18%; bronchopneumonic infiltrate, 24%), while chest computerized tomography was abnormal in 65 cases (88%; p<0.005): mediastinal and hilar lymphadenopathy were present in 46% (p<0.005); miliary pattern, in 23% (p<0.05); and bronchopneumonic infiltrate, in 23% (p<0.05). Cranial computerized tomography was abnormal in 68 cases (92%). Chest computerized tomography scan helps establish the diagnosis of TBM when chest radiography is normal or inconclusive, and it is useful in assessing children with suspected TBM.

Symptomatic and asymptomatic hypohidrosis in children under topiramate treatment.

Topiramate (TPM) has peculiar side effects such as speech difficulties, weight loss, oligohidrosis and hyperthermia. We present the frequency and severity of hypohidrosis in our patients under TPM treatment. One hundred and two patients treated with TPM were evaluated retrospectively. Five (8 months-15 years of age) of them experienced symptomatic hypohidrosis manifested with prolonged or intermittent fever. Pilocarpine iontophoresis sweat test had been performed on the five patients before they were managed, and no sweat had been collected in 4/5 cases. Of the 102 patients, 42 who started TPM treatment when the study was established were evaluated prospectively regarding oligohidrosis. First, they were questioned about whether hypohidrosis occurred after TPM. Of 42, 11 patients complained of hypohidrosis. A sweat test was then performed on these 11 patients. Sweat could not be obtained in 5/11, and increased chloride concentration was found in 4/11. However, sweat could be obtained in the patients who had no complaint of hypohidrosis. Pediatricians should be aware of this side effect of TPM to prevent nonrelevant and cumbersome investigations in patients with prolonged or intermittent fever onset during TPM treatment. Our findings suggest that 5% of patients would experience hyperthermia during TPM treatment. Hypohidrosis without hyperthermia would be more frequent. If it is possible to collect sweat in patients who get fever during TPM treatment, it would be highly probable that the fever is not due to hypohidrosis. Increased chloride concentration alone does not seem to be significant for the hyperthermia risk.

Evaluation of brainstem auditory evoked response audiometry findings in children with tuberculous meningitis at admission.

OBJECTIVE: To determine the characteristics of Brainstem auditory evoked response (BAER) findings in children with tuberculous meningitis (TBM) at admission. METHODS: Twenty-seven children with highly probable TBM were admitted to the University Hospital. The control group was 23 healthy, age and sex matched subjects. Brainstem response audiometry recording was performed in all patients and controls. Ninety dB sound pressure level (SPL) was used for comparisons. The main BAER measurements analysed were the I-III, III-V, I-V interpeak intervals. In statistical analysis, t-test for independent groups were performed. At the same time, for interpeak intervals, values exceeding 2.5 standard deviations (S.D.) above the means of the normal controls were considered abnormal. To the result of BAER findings, HL was classified as mild (until 40 dBHL), severe (until 80 dBHL) and total HL (no hearing was detected). RESULTS: The latencies of interpeak intervals (except III-V latency at 10 per s) have significantly prolonged in comparison with controls. Mild HL was detected in four ears. In eight ears, any wave form could not be obtained at 110 dBSPL. Abnormal BAER result was seen in 13 of 54 ears (24%) at the click of 10 per s and five ears (12%) at the click of 50 per s. CONCLUSION: Abnormal BAER result was seen in 24% of patients with TBM before treatment. Depending on these findings, it can be inferred that hearing impairments must be lower than those values which was detected by BAER during the acute phase of TBM, since the abnormal BAER may be reversible following the illness, returning to normal with recovery.