Death Causes Among Iranian Children With Leukodystrophies

Abstract

Introduction: Leukodystrophies are a heterogeneous group of inherited neurologic disorders. These disorders are indeed progressive and debilitating conditions with limited treatment options and high mortality rates. There is a deficiency in available data concerning both the mortality rates and the most common causes of death in leukodystrophies. Methods: We investigated the mortality rates, mean age at death, and the most common causes of death in a retrospective cohort of 165 Iranian pediatric patients who were diagnosed with leukodystrophies. Results: Death was recorded in 64 of 165 patients (38.8%) with a mean follow-up of 4.7 ± 3.25 years. The mean age of living patients was 7.9 ± 4.8 years and the mean age at death was 5.2 ± 3.9 years. Mortality rate of the entire cohort was 18.1% (30/165), 24.2% (40/165), and 35.7% (59/165) at 3, 5, and 10 years’ follow-up, respectively. The mean age at death was 2.13 ± 0.68 years, 2.67 ± 1.14 years, and 4.33 ± 2.73 years, at 3-, 5-, and 10-year follow-up from first symptom onset, correspondingly. However, there was a significant difference in the mean age at death in years in hypomyelinating leukodystrophies compared with other leukodystrophies (2.19 ± 0.19 standard error [SE], confidence interval [CI] 1.81-2.56; and 6.65 ± 0.62 SE (CI 5.42-7.87); log rank P = .0001, analysis of variance P = .0001). The most common causes of death were cardiopulmonary problems (47%), seizures (11%), sepsis (9%), and miscellaneous (33%). Conclusions: We proposed that a significant majority of childhood leukodystrophy deaths occur within the first 5 years of life, with a notable concentration during the initial 3 years. Further, the results of this study suggest the potential for targeted strategies to address the specific causes of death in children with leukodystrophies.

Keywords

children leukodystrophy pediatric

Leukodystrophies are a heterogeneous group of inherited neurologic disorders that affect the white matter of the central nervous system. Their age at disease onset varies across early infancy or even the neonatal period through adulthood. Leukodystrophies present with a wide spectrum of clinical manifestations ranging from neurodevelopmental delay to regression.¹ Although each distinct leukodystrophy is rare, their cumulative incidence is significant. The relative incidence of leukodystrophies has been reported to be up to ∼1 in 4500 live births in 3 comprehensive epidemiologic studies.^2–4 According to a recent study by Ashrafi et al, the relative incidence of leukodystrophies has been estimated to be up to 3.01 per 100 000 live births with a high rate of consanguinity.⁵

Leukodystrophies currently are not curable, and their treatment is limited to symptomatic management and palliative care.² Libmeldy, an autologous CD34⁺ cell therapy encoding the ARSA gene, is approved by the European Medicines Agency (EMA) for treating children with metachromatic leukodystrophy. Elivaldogene autotemcel (eli-cel) is anticipated to be the first US Food and Drug Administration (FDA)–approved gene therapy to decelerate the progression of neurologic dysfunction in adolescent boys with early, active cerebral adrenoleukodystrophy. For neurologic and nonneurologic symptoms, the preferred treatment is early initiation of oral chenodeoxycholic acid, although it lacks FDA approval for cerebrotendinous xanthomatosis. Chenodeoxycholic acid has received approval in the European Union for treating adults and children with cerebrotendinous xanthomatosis over 1 month of age. The FDA has granted it orphan drug designation for use in cerebrotendinous xanthomatosis.^6,7 In general, new emerging therapies, including gene therapy, are currently under investigation and have yet to be established as standard treatments.⁸

Different estimates for leukodystrophy mortality rates have ranged from 1.513 per 1 000 000 ages 0-17 years to 30% by age 8 years.^2,9 Furthermore, it has been reported that approximately one-third of all hospital-based medical expenses in US children's hospitals are dedicated to children with chronic neurologic disorders such as leukodystrophies.¹⁰

The goal of our study was to determine mortality rates and characterize potential predictor factors and causes of death in a cohort of childhood leukodystrophies using a hospital registry system with long-term follow-up. The results of this study could inform future work to provide efficient strategies to prevent complications that results in death and mortality rate as well as improving the quality of life in children with leukodystrophies.

Material and Methods

Study Design and Participants

This retrospective and descriptive-analytical study was conducted with the aim to investigate short-term (3 and 5 years) and long-term (10 years) mortality rates of leukodystrophies and the causes of death in a cohort of children with leukodystrophies. The recorded data of patients with a confirmed diagnosis of leukodystrophy who were registered on the Iranian Neurometabolic Registry of Children's Medical Center Hospital from 2010 to 2019 were extracted. Initially, those patients who presented with neurodegeneration or global developmental delay were recorded in Iranian Neurometabolic Registry. Then, data consisting of those patients with clinical and imaging findings suggestive of leukodystrophy and a confirmed diagnosis were extracted. The diagnosis was confirmed based on a combination of genetic, enzymatic, and metabolic tests results. Metabolic and fibroblast enzyme studies were executed as needed included serum ammonia and lactate, serum amino acids analysis by high-performance liquid chromatography, tandem mass spectrometry, urine organic acids profile, fibroblast activity level of HEXA and HEXB enzymes, and serum very-long-chain fatty acids. The molecular tests included single gene tests and panel-based studies. Whole-exome sequencing was not performed because of limited access to the test during the initial years of the study. Demographic information including age, sex, family history, consanguinity, age of disease onset and age of diagnosis, follow-up duration from first symptom onset and laboratory, and clinical data were obtained from the registry. Enrolled patients were contacted via the phone in order to update their files regarding disease status, as well as living versus death. In addition, the cause and time of death were extracted from the patients’ death certificate in cases of death. The inclusion criteria were all confirmed cases of leukodystrophies who were registered on the Iranian Neurometabolic Registry, had available follow-up visit notes, and a proven death certificate in cases of death. Death of each patient was confirmed using a death certificate medical examination. In addition, the report of death of each patient was double checked through cross-checking the national health death records system and hospital death records based on the patient's name and national code number. Exclusion criteria consisted of undiagnosed patients, unverified death certificates, and lack of clinical data including follow-up visits. The classification suggested by Van der Knaap et al¹¹ was considered for imaging classification of enrolled patients: hypomyelination pattern consisting of mild T2-weighted hyperintensity with mild hypo-, iso-, or hyperintense T1-weighted signals relative to the cortex, and other leukodystrophies consistent with prominent T2-weighted hyperintensity and prominent T1-weighted hypointensity based on magnetic resonance imaging (MRI) pattern.

Statistical Analyses

All data were retrieved from the Iranian Neurometabolic Registry and recorded in a computerized database for further analysis. IBM SPSS Statistics 21.0 software was used for statistical analysis. Baseline categorical characteristics were reported as n (%) and continuous variables described as mean ± standard deviation (SD). Nonparametric test was used to evaluate mean age at onset and age at diagnosis between subgroups. Median survival was measured using the Kaplan-Meier estimate. Log-rank test was used to compare the survival rates in subgroups. Cox proportional hazards model was used to determine factors related to the patient's mortality. Variables whose P value was less than .2 in univariate analysis were entered into multivariate analyses. Significance level of <.05 was considered with 95% confidence interval.

Results

In this study, 165 patients with a confirmed diagnosis of leukodystrophy met the inclusion criteria. The mean age of all enrolled patients was 7.9 ± 4.8 years, and their mean follow-up was 4.7 ± 3.25 years. A total of 101 patients were still alive at the time of study. The mean age of alive patients was 9.7 ± 4.6. In addition, 64 patients died during the follow-up period, and their mean age at death was 5.18 ± 3.9 years. Demographic information including age, sex, family history, consanguinity, age of disease onset and age of diagnosis, and follow-up duration are reported in Table 1. All patients were of Persian ethnicity. Ninety-five patients (57.6%) were male, and 70 patients (42.4%) were female. Consanguinity rate (ie, parallel first cousins, cross first cousins, double first cousins, first cousins once removed, and second cousins) among all families was estimated at 83.6%.¹²

Table 1.

Demographic Characteristics of Patients.

Characteristics		Total(N = 165)	Hypomyelination(n = 43)	Other leukodystrophies(n = 122)	P value
Gender, n (%)					.432
Male		95 (57.6)	27 (62.8)	68 (55.7)
Female		70 (42.4)	16 (37.2)	54 (44.3)
Consanguinity		138 (83.6)	37 (86)	101 (82.8)	.61
Affected sibling, n
	One	140 (84.8)	37 (86)	103 (84.4)	.79
	Two or more	25 (15.2)	6 (14)	19 (15.6)	.79
Age, y mean ± SD		7.9 ± 4.8	4.7 ± 3.36	9.09 ± 4.84	.001
Age at death, y, mean ± SD		5.18 ± 3.9	2.1 ± 0.87	6.6 ± 4.09	.001
Age of alive patients, y mean ± SD		9.7 ± 4.6	7.1 ± 3.05	10.41 ± 4.73	.003
Age at onset, y, mean ± SD		1.29 ± 1.94	1.00 ± 1.39	1.34 ± 2.10	.001^a
Age at diagnosis, y, mean ± SD		2.28 ± 3.05	1.80 ± 1.97	2.45 ± 3.36	.0001^a
Follow-up, y mean ± SD		4.7 ± 3.25	2.96 ± 2.46	5.41 ± 3.27	.001
Total death, n (%)		64 (38.8)	21 (48.8%)	43 (35.2%)	.116

Nonparametric test.

In imaging analysis, 43 patients (26.1%) had a hypomyelinating pattern, and 122 patients (73.9%) had the pattern of other leukodystrophies including a demyelinating pattern. Disorders in the group of hypomyelinating leukodystrophies included GM1-gangliosidosis, GM2-gangliosidosis, Pelizaeus Merzbacher disease, and Pelizaeus Merzbacher–like disease. Disorders in the group of other leukodystrophies including demyelinating leukodystrophies consisted of metachromatic leukodystrophy, Canavan disease, Alexander disease, L2-hydroxyglutaric aciduria-type 2, X-linked adrenoleukodystrophy, Zellweger syndrome, megalencephalic leukoencephalopathy with subcortical cysts, Mitochondrial disorders, glutaric acidemia type 1, Niemann-Pick disease type C, mucopolysaccharidosis types I and III, and Cockayne syndrome. In total, 17 different diagnoses were identified in this study. Lysosomal storage disorders were mainly GM2-gangliosidosis, Niemann-Pick disease type C, and metachromatic leukodystrophy; amino acid and organic acid metabolism disorders were mainly Canavan disease; myelin protein disorders were mainly Pelizaeus Merzbacher–like disease; and peroxisomal disorders were mainly X-linked adrenoleukodystrophy (Table 2).

Table 2.

Diagnosed Leukodystrophies and their Fatality Ratio.

	Number (%) (n = 165)	Fatality number (%) (n = 64)	Most common causes of death
Lysosomal disorders
GM2-gangliosidosis	26 (15.8)	17 (27)	Severe FTT (6/27)Cardiopulmonary problems (5/17)Seizure (5/17)Cerebral hemorrhage (1/17)
MLD(not receiving HSCT)	20 (12.1)	10 (15.5)	Cardiopulmonary problems (5/10)Severe FTT (4/10)Sepsis (1/10)
NPC	19 (11.5)	8 (12.5)	Cardiopulmonary problems (6/8)Hepatic failure (1/8)Severe FTT (1/8)
MPS (types I, III)	14 (8.5)	2 (3.2)	Sepsis (1/2)Accidental head trauma (1/2)
GM1-gangliosidosis	5 (3)	4 (6)	Cardiopulmonary problems (4/4)
Other lysosomal disorders^a	10 (6.1)	7 (11)	Cardiopulmonary problems (5/7)Severe FTT (2/7)
Amino acid and organic acid disorders
Canavan disease	18 (11)	5 (7.7)	Sepsis (2/5)Severe FTT (2/5)Cardiopulmonary problems (1/5)
GA-1	7 (4.2)	3 (4.7)	Cardiopulmonary problems (1/1)Severe FTT (1/1)Sepsis (1/1)
L2-Hydroxyglutaric aciduria-type 2	6 (3.6)	1 (1.5)	Seizure (1/1)
Other amino acid and organic acid disorders^b	13 (8)	3 (4.7)	Cardiopulmonary problems (2/3)Sepsis (1/3)
Myelin proteins disorders
PMDL	6 (3.6)	0
PMD	3 (1.8)	0
Peroxisomal disorders
X-ALD	6 (3.6)	3 (4.7)	Severe FTT (2/3)Seizure (1/3)
Zellweger syndrome	1 (0.6)	1 (1.5)	Cardiopulmonary problems (1/1)
Ion and water homeostasis disorders
MLC	5 (3)	0
DNA repair
Cockayne syndrome	2 (1.2)	0
Mitochondrial disorders	1 (0.6)	0
Miscellaneous including AxD	3 (1.8)	0

Abbreviations: AxD, Alexander disease; FTT, failure to thrive; GA-1, glutaric acidemia type 1; GM1, gangliosidosis type 1; GM2, gangliosidosis type 2; HSCT, hematopoietic stem cell therapy; MLC, megalencephalic leukoencephalopathy with subcortical cysts; MLD, metachromatic leukodystrophy; MPS, mucopolysaccharidosis; NPC, Niemann-Pick disease type C; PMD, Pelizaeus-Merzbacher disease; PMLD, Pelizaeus Merzbacher like disease; X-ALD, X-linked adrenoleukodystrophy.

Mucolipidosis, Farber disease, Gaucher disease.

Propionic acidemia, nonketotic hyperglycinemia, multiple carboxylase deficiency, homocystinuria, methylmalonic aciduria.

From 2010 to 2019, death was recorded in 64 patients (38.8%), and 101 patients were still alive at the end of study (61.2%). Fatality ratio classification is shown in Table 2. Mortality rate of the entire cohort was 18.1% (30/165) at 3-year follow-up, 24.2% (40/165) at 5-year follow-up, and 35.7% (59/165) at 10-year follow-up. The mean age at death was 2.13 ± 0.68 years, CI 1.90-2.36, at 3-year follow-up (2.00 ± 0.66 in hypomyelinating leukodystrophies vs 2.36 ± 0.67 in other leukodystrophies, P value = .163); 2.67 ± 1.14 years, CI 2.32-3.05, at 5-year follow-up (2.19 ± 0.87 in hypomyelinating leukodystrophies vs 3.21 ± 1.18 in other leukodystrophies, P value = .003), and 4.33 ± 2.73, CI 3.66-5.03, at 10-year follow-up (2.19 ± 0.87 in hypomyelinating leukodystrophies vs 5.52 ± 2.68 in other leukodystrophies, P value = .001) (Figure 1).

The surviving proportion of all patients including hypomyelinating leukodystrophies and other leukodystrophies is shown in a Kaplan-Meier curve in Figure 2. The overall mean age at death for the entire cohort was 5.18 years (±3.9 SD, CI 4.21-6.16). However, the mean age at death in hypomyelinating leukodystrophies was 2.19 years (± 0.19 standard error [SE], CI 1.81-2.56), whereas in other leukodystrophies the mean age at death was 6.65 years (±0.62 SE, CI 5.42-7.87). Analysis showed that there was a significant difference between the hypomyelinating and nonhypomyelinating leukodystrophy groups regarding the mean age at death (log rank P = .0001, analysis of variance P = .0001). In this analysis (Cox), age (mean age of enrolled patients, age of alive patients, age at death, age of disease onset, age of diagnosis), follow-up duration, the presence of consanguinity, sex, and number of affected siblings were all considered in our analysis as potential predictor factors that may affect the survival time of patients. Based on the univariate analysis of leukodystrophy subgroups, the presence of consanguinity, sex, and number of affected siblings were not significant between dead and alive patients. Considering that the variable of age showed a significant difference between 2 leukodystrophy subgroups, it was expected that all age-related variables such as patient's age, the mean age of enrolled patients, age of alive patients, age at death, age of disease onset, age at diagnosis, and follow-up duration would be significant between the 2 subgroups. However, it was impossible to predict and compare the survival time between 2 leukodystrophy subgroups based on the regression model because of the presence of only 1 significant variable, that is, age-related variables. The details are shown in Supplementary Table 1.

The most common causes of death among patients were cardiopulmonary problems (47%) including aspiration pneumonia, respiratory or cardiac arrest; seizures and complications (11%); sepsis and septic shock (9%); and miscellaneous including failure to thrive (FTT), hepatic failure, head trauma, and cerebral hemorrhage (33%). The causes of death in enrolled patients are shown in Figure 3.

Discussion

In this study, we investigated the mortality rates, mean age at death, and the most common causes of death, in a retrospective cohort of 165 pediatric patients with different types of leukodystrophies. We proposed that a significant majority of childhood leukodystrophy deaths occur within the first 5 years of life, with a notable concentration during the initial 3 years. Further, to our knowledge, this study is the first report of causes of death in leukodystrophies. In addition, we evaluated the 3-, 5-, and 10-year mortality rate; show differential mortality rates between hypomyelinating and nonhypomyelinating leukodystrophies; and the mortality rate in a cohort of children with leukodystrophies from a non–European ancestry country. In various studies of leukodystrophies, metachromatic leukodystrophy and X-linked adrenoleukodystrophy have consistently emerged as the more commonly diagnosed types.¹¹ However, in both this study and another large cohort study on leukodystrophies conducted by the authors in Iran, Canavan disease has been diagnosed more frequently alongside metachromatic leukodystrophy and X-linked adrenoleukodystrophy, distinguishing it from other comparable studies.¹³ The proximity of results of the current study and Ashrafi et al¹³ in Iranian children indicates unique distribution of leukodystrophies because of reasons such as the high consanguinity rate in Iran.

Our results showed a mortality rate of 38.8% with an average age at death of 5.18 years. Interestingly, our data are similar to findings reported by Barczykowsk et al¹⁴ in a study from the United States, which used national mortality rate data in combination with state death certificate records and International Classification of Diseases, Tenth Revision, disease classification. They reported an overall age at death due to leukodystrophy of 5.2 years, very similar to our cohort. This suggests that genetic factors may have a more important contribution in leukodystrophy mortality rather than environmental, social, or geographical factors. They were also able to determine an overall estimated leukodystrophy death rate of 1.513 per 1 000 000 patients aged 0-17 years. Another study in 2010, by Bonkowsky et al,² reported a mortality rate of 34% of leukodystrophies in US children. However, the average age at death was reported at 8.2 years, which is 3 years older compared with our findings or those of Barczykowsk et al. The reasons for the discrepancy in average age at death is uncertain, but is likely multifactorial and may reflect different patient cohorts, as well as differences in the methodology for identification of patients and determination of mortality.^15–18

The most lethal disease with a short survival time was Sandhoff disease in the lysosomal disorders group, followed by metachromatic leukodystrophy and Niemann-Pick disease type C. The US 2021 national database showed the highest death rate due to leukodystrophies in the pediatric population belongs to peroxisomal biogenesis disorders (0.442) followed by metachromatic leukodystrophy (0.317).⁹

Findings in our study revealed that the most common causes of death in children with leukodystrophies were cardiopulmonary problems (47%), including aspiration pneumonia followed by respiratory and cardiac arrest. Seizures and sepsis were the second and third leading causes of death. Seizures can occur at any age and stage of leukodystrophies; however, they tend to be more refractory in advanced stages of leukodystrophies. According to a recent study by Keller et al,¹⁵ they reported seizures as one of the 4 core neurologic issues in patients with leukodystrophies as being most problematic to families. We identified failure to thrive as a significant cause of mortality, highlighting the need for special attention to the nutritional status of patients with leukodystrophies.

Another new finding from our work was the mortality rates of children with leukodystrophies at different ages. The mortality rate at 3-, 5-, and 10-year follow-ups in the enrolled patients were 18.1%, 24.2%, and 35.7%, respectively. Figure 1 illustrates that approximately half of the deaths in the deceased population occurred within the initial 3 years of life, with a subsequent increase in survival rates with advancing age.

The highest mortality rate occurs in the first 3 years of life, further emphasizing the need for early diagnosis and intervention. We had analyzed the variables of age, consanguinity rate, and number of affected siblings, as potential predictive factors that might be associated with the mortality rate of leukodystrophy patients. However, our analysis (not shown) indicated that the only significant factor was age between 2 leukodystrophy subgroups, which in turn hindered using the Cox regression analysis to further define the predictor factors of survival time of leukodystrophies. This finding suggests a marked role of genetic factors in the survival time of these disorders.

Although leukodystrophies have a lower incidence compared with some neurologic disorders such as epilepsy in the pediatric population, they are associated with a remarkably higher mortality rate. For example, in a prospective community-based study with 4 years’ follow-up by Berg et al¹⁹ in 2004, they reported a mortality rate of 2.1% in 613 children aged 1 month to 15 years with newly diagnosed epilepsy. In another article published by Berg et al²⁰ in 2013, which combined data from 4 studies including 3 prospective and 1 retrospective studies regarding epilepsy mortality in children, they reported a mortality rate of 3.52% in 2239 patients aged 1 month to 17 years with newly diagnosed epilepsy during a mean follow-up of 11.25 years. In contrast, mortality in leukodystrophies is approximately 10 times higher. This highlights a particular need to improve care and therapies for children with leukodystrophies, including preventative care, to reduce their mortality rate.

Limitations of our work included its retrospective nature, and that limited numbers of each specific leukodystrophy made it impossible to calculate death-related information and mortality rates for each type. Finally, although our center is the only hospital caring for leukodystrophies in the population, all data in this study were derived from a single referral center.

Available epidemiologic data regarding the incidence, prevalence, lifetime risk, and the most common causes of death in leukodystrophies are insufficient. These missing data could be attributable to a lack of multinational studies, the nature of leukodystrophies as orphan diseases, and the various biostatistical methods that have been used in different studies on the epidemiologic data of leukodystrophies.^16–18 These data are essential to calculate disease burden in population-based studies. Although only a few therapeutic options are available in childhood leukodystrophies, symptomatic and preventive care should be considered as they significantly affect the quality of life of affected patients.^21,22 Our findings on the mortality rate of leukodystrophies support the need for efforts on early diagnosis and treatment of these rare neurogenetic disorders, for example, through newborn screening. More education and resources regarding lethal complications of leukodystrophies would be invaluable for physicians and families facing these orphan disorders.²³ The results of this study could be helpful to provide efficient strategies in order to prevent these lethal complications as well as improving the quality of life and survival rate in affected children with leukodystrophies.

Supplemental Material

sj-docx-1-jcn-10.1177_08830738241293171 - Supplemental material for Death Causes Among Iranian Children With Leukodystrophies

Supplemental material, sj-docx-1-jcn-10.1177_08830738241293171 for Death Causes Among Iranian Children With Leukodystrophies by Mahsa Shiva, MD, Sareh Hosseinpour, MD, Mahmoud Reza Ashrafi, MD, Morteza Heidari, MD, Zahra Rezaei, MD, Jayran Zebardast, PhD, Masoud Mohammadpour, MD, Joshua L. Bonkowsky, MD, PhD, and Ali Reza Tavasoli, MD in Journal of Child Neurology

Footnotes

Acknowledgments

We appreciate the patients and their families for their willingness to participate in this research.

Author Contributions

AT conceptualized and designed the study, and critically reviewed and revised the manuscript. MS contributed to acquisition and interpretation, drafted the initial manuscript. SH contributed to data acquisition, analysis, and interpretation and critically reviewed the manuscript. JZ carried out the analyses and drafting the article. MA, MH, MM, and ZR contributed to data acquisition and interpretation and drafting the article. JB carried out the analyses and interpretation of data and critically reviewed and revised the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors discloses receipt of the following financial support for the research of this article: Research reported in this publication was supported and funded by the National Institute for Medical Research Development (electronic application No: 983886).

Ethical Approval

The study protocol was approved by the ethical committee of Children's Medical Center, Tehran, Iran (IR.TUMS.MEDICINE.REC.1396.3082). For all patients, a signed informed consent was provided by their parents according to the national ethical requirements, and Declaration of Helsinki instruments. Patients were only accepted if the consent did not exclude data sharing.

ORCID iDs

Joshua L. Bonkowsky

Ali Reza Tavasoli

Supplemental Material

Supplemental material for this article is available online.

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