Tyrosinemia Type Iii: A Case Report of Siblings and Literature Review

Abstract

<jats:p>ABSTRACT Objective: Tyrosinemia type III (HT III) is the rarest form of tyrosinemia, and the full clinical spectrum of this disorder is still unknown. The neurological involvement varies, including intellectual impairment and attention deficit disorder with hyperactivity (ADHD). We report the case of two siblings diagnosed with HT III at different ages. Case description: The index case was diagnosed by newborn screening for endocrine and metabolic disorders, starting a low-protein diet immediately, with a consistent decrease in tyrosine levels. By the age of three, the child displayed a hyperactive behavior, starting treatment for ADHD two years later. At seven years of age, he shows a slight improvement in terms of behavior and attention span and has a cognitive performance slightly lower than his peers, despite maintaining acceptable tyrosine levels. His sister, who had a history of ADHD since age five, was diagnosed with HT III after family screening at the age of eight. Despite initiating a dietetic treatment, her behavior did not improve, and she has a mild intellectual impairment. Comments: This is the first case report describing siblings with HT III who underwent nutritional treatment with a low-protein diet in different phases of life, with a better neurological and behavioral evaluation in the patient who started treatment earlier.</jats:p>

Novel Cranial Imaging Findings and a Splice-Site Variant in a Patient with Tyrosinemia Type III, and a Summary of Published Cases

“…In their study involving 13 patients, Ellaway et al [2001] showed that 75% of patients with tyrosinemia type III had neurological manifestations, which included intellectual disability, ataxia, increased deep tendon reflexes, tremors, microcephaly, dyslexia, attention deficit, ataxia, hypotonia, and seizures. Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder in these patients have been previously reported in the literature [Tahiroğlu et al, 2008;Barroso et al, 2020]. We planned to follow-up our patient for autism spectrum disorder because she had stereotypical movements and made less eye contact compared to peers.…”

“…A summary of all previously reported patients with biallelic HPD mutations is presented in Table 2 [Cerone et al, 1997;Standing et al, 1998;Rüetschi et al, 2000;Tomoeda et al, 2000;Heylen et al, 2012;Szymanska et al, 2015;Coskun et al, 2016;Barroso et al, 2020]. Of these patients, 4 were diagnosed by neonatal screening, and diet was initiated in all of them.…”

“…Tyrosinemia type III is an extremely rare autosomal recessive disease, with only 19 patients yet reported [Ellaway et al, 2001;Heylen et al, 2012;Szymanska et al, 2015;Coskun et al, 2016;Najafi et al, 2018;Barroso et al, 2020]. It is caused by the deficiency of 4-hydroxyphenylpyruvate dioxygenase enzyme (4-HPPD), resulting from biallelic mutations in the HPD gene.…”

The Discovery of the Mode of Action of Nitisinone

“…A metabolic deficiency of tyrosine aminotransferase ( Figure 1 ), Richner-Hanhart syndrome leads to a marked tyrosinaemia which can result in corneal opacities if the dietary intake of phenylalanine and tyrosine is not restricted [ 7 ]. A small number of cases of HPPD deficiency have been reported [ 8 , 9 ] called tyrosinaemia type III ( Figure 1 ). Tyrosinaemia Type 1 is where fumarylacetoacetase, the last enzyme in the pathway is deficient resulting in acute tissue injury with children usually dying in the first two years of life.…”

In vivolentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions

“…15,16 This theory is further supported by the fact that HT3, the disease caused by a deficiency in the same enzyme that NTBC blocks, also presents with neurological manifestations including developmental delay. [17][18][19][20] Complications attributed to NTBC treatment other than low IQ include attention deficits, memory and processing problems, psychomotor and behavioral issues, and impairment of executive function and social cognition. [21][22][23][24][25][26][27][28] To date, the only therapeutic option for patients refractory to NTBC or with disease progression despite NTBC therapy, and the only curative treatment for HT1, is liver transplantation.…”