Lack of Long-Term Neurologic Efficacy of Zileuton in Sjögren–Larsson's Syndrome

Sjögren-Larsson's syndrome (SLS) is a rare and disabling genetic disorder characterized by congenital pruritic ichthyosis, mental retardation, and progressive spastic diplegia. Disease course often features retinal crystalline inclusions on the eye fundus. Cerebral MRI (magnetic resonance imaging) shows dysmyelination. Proton magnetic resonance spectroscopy (¹H-MRS)[1] shows pathognomonic abnormal lipid peaks at 1.3 and 0.9 ppm in white matter (WM). SLS is caused by a deficiency of fatty aldehyde dehydrogenase (FALDH), a microsomal enzyme of lipid metabolism, leading to accumulation of long-chain fatty alcohols, branched-chain alcohols, and leukotriene B₄ (LTB₄) in skin, retina, and WM of the central nervous system (CNS). SLS is confirmed by low FALDH activity in cultured skin fibroblasts and/or analysis of the ALDH3A2 gene encoding FALDH.[1]

More than 15 years ago, a therapeutic approach using zileuton, a 5-lipoxygenase inhibitor that blocks the synthesis of LTB₄, was reported as helpful on pruritus and behavior in three of five patients with SLS in an open-label trial according to two papers from Willemsen et al.[2] [3] More recently, a double-blind placebo-controlled crossover study in 10 patients over a 16-week period showed improvement of pruritus in only one patient without efficacy on ichthyosis or neurologic symptoms.[4]

Willemsen et al also reported that zileuton decreased LTB₄ levels in urine at 5 weeks of treatment in one child[2] and at 3 months of treatment in five adults and adolescents.[3] Three patients had a decreasing lipid peak at 1.3 ppm on ¹H-MRS.[2] [3] No long-term follow-up of patients with SLS treated by zileuton has been published to date, and the effects of zileuton in children younger than 5 years remain unknown.

We used zileuton to treat seven unrelated children (six females and one male) aged between 17 months and 16 years (median age: 4 years) with typical SLS confirmed by low FALDH activity and/or ALDH3A2 analysis ([Table 1]). Dose was between 40 and 100 mg/kg/day, divided into three or four times (maximal dose: 3,600 mg/day). The French Drug Safety Agency approved the use of zileuton for SLS, and informed parental consent was obtained for all patients. Dermatological (ichthyosis and pruritus), neurologic (spasticity, language, and cognition), and ophthalmological signs were evaluated yearly. Cerebral MRI and ¹H-MRS were performed before and every 2 years during treatment. Serum aminotransferase levels were controlled monthly during the first 6 months of treatment.

Table 1 Clinical and radiological evolution of patients with Sjögren–Larsson's syndrome treated by zileuton

Patient	Age at SLS diagnosis[a]	Sex	Age at start of treatment[a]	Years on treatment[a]	Dose of treatment	Ichthyosis and pruritus evolution	Psychometric evolution[b]	SPG evolution	Eye fundus evolution	Serum ASAT/ ALAT	WM evolution	Gray matter evolution	0.9/1.3 ppm lipid peak evolution
1	2	F	4	5	40mg/kg/d	=	=	Worsening	=	N	=	=	=
2	10	F	14	5	40mg/kg/d	=	=[c]	Worsening	=	N	=	Atrophy	=
3	4	F	16	0.7	40mg/kg/d	=	=	Worsening	=	4 × N	=	=	=
4	1.5	M	1.5	0.5	40mg/kg/d	=	NA	Worsening	=	N	NA	NA	NA
5	3	F	4	2	45mg/kg/d	=	=	Worsening	=	N	=	=	=
6	3.5	F	3.5	10	100mg/kg/d	=	=	Worsening	=	N	Worsening	=	=
7	2	F	2	2	40mg/kg/d	=	=	Worsening	NA	N	=	=	=

Abbreviations: ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase; F, female; M, male; N, normal; NA, not available; ppm, parts per million; SPG, spastic paraplegia; WM, white matter.

^a Expressed in years.

^b Intellectual improvement was evaluated by age-adapted psychometric tests (Columbia scale, Wechsler Preschool and Primary Scale of Intelligence [WPPSI] III scale, or Wechsler Intelligence Scale for Children [WISC] IV scale).

^c Parents of patient 2 described improvement in alertness and execution speed. ”=”: Stability.

Zileuton was discontinued after 8 months in a 16-year-old girl due to a fourfold increase in serum aminotransferases. The six remaining patients were treated during a median time of 3.5 years (range: 6 months to 10 years) without side effects including normal serum aminotransferase levels. No improvement in ichthyosis, pruritus, photophobia, language, and visual or motor abilities was reported. No change in eye fundus was found. The family of a 4-year-old child given 5 years of treatment described progress in attention and executive functions, but successive neuropsychological evaluations failed to manifest this finding. Cerebral MRI before and during treatment showed various degrees of abnormal WM signals with no improvement over time. MRI follow-up found cortical atrophy appearing in frontal regions in one patient and a worsening of dysmyelination in another patient. ¹H-MRS showed persistent lipid peaks at various time points, with no change in other metabolic peaks.

Zileuton inhibits cysteinyl LT and LTB₄ synthesis. It may be helpful in SLS by limiting the in-tissue accumulation of LTB4 and ω-hydroxy LTB₄ metabolites caused by FALDH deficiency.[1] Zileuton may also limit systemic effects of LTB₄, such as pruritus. It was hoped that zileuton would bring neurologic improvement, without evidence of the role of LTB4 in SLS-associated motor and cognitive impairment.[1] [3] This is the first paper to report long-term follow-up of zileuton in children and adolescents with SLS. We observed neither improvement nor stabilization in motor capacities. Spastic paraplegia progressed in all cases. Improvement in attention capacities was observed in one of the youngest patients treated, but this improvement could be related to maturation of the CNS. It is difficult to assess whether zileuton was directly involved in this effect, especially as cerebral ¹H-MRS found no change in lipid peaks, contrary to the first three patients reported by Willemsen et al.[2] [3] after 1 to 3 months of treatment. Urinary LTB₄ levels, which can reflect zileuton intake, were not available in our series of patients, but adherence to treatment was satisfactory in all cases. LTB₄ and ω-hydroxy-LTB₄ levels were reported as decreased with a daily dose of 40 mg/kg of zileuton[1] [2] in the initial studies but could not be technically assessed in the more recent study.[4] The dose used here was identical or even lower.

Our long-term follow-up data demonstrates no apparent neurologic effects of zileuton in SLS over time, not just in adolescents but also younger children. Effects on dermatological symptoms may differ among patients. Fuijkschot et al advocated discontinuing zileuton if no cutaneous effect was observed after a few weeks of treatment.[4] In a recent review on therapeutic approaches in SLS, Rizzo suggested an alternative approach to pharmacological inhibition of LTB4 receptors using small bioactive molecules that may be more fruitful than zileuton.[5]

• References

• 1 Rizzo WB. Sjögren-Larsson syndrome: molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency. Mol Genet Metab 2007; 90 (1) 1-9
• 2 Willemsen MA, Rotteveel JJ, Steijlen PM, Heerschap A, Mayatepek E. 5-Lipoxygenase inhibition: a new treatment strategy for Sjögren-Larsson syndrome. Neuropediatrics 2000; 31 (1) 1-3
• 3 Willemsen MA, Lutt MA, Steijlen PM , et al. Clinical and biochemical effects of zileuton in patients with the Sjögren-Larsson syndrome. Eur J Pediatr 2001; 160 (12) 711-717
• 4 Fuijkschot J, Seyger MM, Bastiaans DE, Wevers RA, Roeleveld N, Willemsen MA. Zileuton for pruritus in Sjögren-Larsson syndrome: a randomized double-blind placebo-controlled crossover trial. Acta Derm Venereol 2016; 96 (2) 255-256
• 5 Rizzo WB. Genetics and prospective therapeutic targets for Sjögren-Larsson Syndrome. Expert Opin Orphan Drugs 2016; 4 (4) 395-406