PHRINL Syndrome: A Case of Infantile Cataract and Cardiomyopathy

Abstract

Introduction

Pontocerebellar Hypoplasia, Hypotonia, and Respiratory Insufficiency Syndrome, Neonatal Lethal (PHRINL Syndrome) is a rare genetic disorder caused by impaired oxidative phosphorylation due to reduced activity of mitochondrial complexes I, IV, and V. The condition results from homozygous or compound heterozygous pathogenic variants in the ATAD3A gene, and is inherited in an autosomal recessive manner. Affected individuals typically present in early infancy with hypotonia, encephalopathy, corneal clouding, cardiomyopathy, and respiratory failure, and often die during infancy.

Case Presentation

A 40-day-old female infant was referred for evaluation of a possible inherited metabolic disorder following the death of her brother at 9 months of age. No abnormalities were detected in the metabolic workup. Hypotonia was identified on physical examination at 3 months of age, brain magnetic resonance imaging (MRI) revealed pontocerebellar hypoplasia. Whole-exome sequencing (WES) identified two genetic alterations in the ATAD3A gene, leading to the diagnosis of PHRINL Syndrome. ATAD3A (NM_001170535.3: c.229C>G; p.Leu77Val) c.229C>G heterozygous missense variant was detected, along with a 0.61 kb heterozygous deletion encompassing exons 3–4 of the ATAD3A gene. The patient diagnosed with hypotonia at 3 months of age, developed cataracts at 5 months, and died in the eighth month due to refractory seizures.

Conclusion

In hypotonic infants presenting with cataracts and cardiomyopathy, elevated plasma lactate levels and increased urinary excretion of 3-methylglutaconate and 3-methylglutarate may suggest PHRINL syndrome; however, the diagnosis should not be excluded solely on the basis of normal metabolic test results when characteristic clinical features are present.

Established Facts

• For hypotonic infants with cataracts and cardiomyopathy, elevated plasma lactate levels and increased urinary excretion of 3-methylglutaconate and 3-methylglutarate are recognized metabolic indicators that support a diagnosis of PHRINL syndrome.

Novel Insights

• This report emphasizes that normal metabolic screening results do not exclude a diagnosis of PHRINL syndrome when hallmark clinical features are present. It underscores the importance of clinical suspicion and phenotypic recognition over biochemical findings alone.

Introduction

Pathogenic variants in the ATAD3A gene, which is involved in mitochondrial dynamics, nucleotide organization, and cholesterol metabolism, impair oxidative phosphorylation by reducing the activity of mitochondrial complexes I, IV, and V. The clinical phenotype varies depending on the extent of the respiratory chain involvement [1]. These variants can lead to a wide spectrum of clinical presentations, ranging from a neonatal-lethal form to milder phenotypes that persist into adulthood. The disorder was first described in 2016 and has since been classified into two main clinical phenotypes [2].

The first phenotype, PHRINL Syndrome (OMIM#618810), is a severe neonatal-onset disorder caused by biallelic loss-of-function variants in the ATAD3A gene. Affected individuals typically present with encephalopathy, corneal clouding, cardiomyopathy, pontocerebellar hypoplasia (PCH), hypotonia, and respiratory failure and most do not survive beyond infancy [2].

The second phenotype, Harel-Yoon Syndrome, is characterized by developmental delay, moderate intellectual disability, hypotonia, spasticity, peripheral neuropathy, optic atrophy, and mild cardiomyopathy. It is caused by monoallelic dominant missense variants in the ATAD3A gene [2].

A distinct phenotype of the disease, hereditary spastic paraparesis, resembling cerebral palsy and with a later onset, was described by Helen M. Cooper and colleagues in 2017 [3]. Herein, we present a case of PHRINL syndrome diagnosed at an early stage, prior to the onset of clinical manifestations, in an infant with a family history of a sibling who died at 9 months of age due to an unknown disease.

Case Report

A 40-day-old female infant, born to non-consanguineous parents, was admitted to our clinic with a familial history of an undiagnosed sibling death at 9 months of age. The deceased sibling had presented with epilepsy, cataracts, and cardiomyopathy, with symptom onset in the second month of life.

Following prenatal screening tests indicating an elevated risk, amniocentesis was recommended; however, the family declined the procedure. The neonate was delivered at 40 weeks of gestation with meconium-stained amniotic fluid, and a birth weight of 2.950 g. There was no history of birth asphyxia and neonatal intensive care unit admission was not required.

On physical examination, the patient’s weight was 3.4 kg (−1.83 SDS), length was 55 cm (0.02 SDS), and head circumference was 36.5 cm (−1.16 SDS). Systemic examination was unremarkable, with normal muscle tone and intact neonatal reflexes. The red reflex was present bilaterally. Notable dysmorphic features included a high-arched palate and a sacral dimple.

Although the patient’s sibling was asymptomatic during the neonatal period, a history of cataracts, cardiomyopathy, and seizures prompted an evaluation for an inherited metabolic disorder. The patient’s lactate level was 2.8 mmol/L, and urine organic acid analysis revealed no abnormalities. Ophthalmological examination was normal, and the patient passed the newborn hearing screening. Electrocardiography and echocardiography were also normal. No definitive diagnosis was established.

At 3 months of age, physical examination revealed central hypotonia. Notably, the patient, who had initially achieved head control, had lost this ability. Subsequent ophthalmological and cardiac evaluations were normal, and transfontanel ultrasonography was unremarkable. However, brain magnetic resonance imaging demonstrated hypoplasia of the pons and cerebellum (Fig. 1).

Fig. 1.

Sagittal and coronal brain magnetic resonance imaging images showing PCH. a Sagittal T2-weighted image demonstrating reduced volume of the pons and cerebellum. b Coronal T2-weighted image confirming hypoplasia of the cerebellar hemisphere.

Bilateral cataracts were identified at 4 months of age and required surgical intervention. By 5 months, the patient exhibited marked hypotonia. Electroencephalographic assessment demonstrated no epileptiform abnormalities; however, background activity during sleep was disorganized. Electrocardiograph was normal.

Whole-exome sequencing (WES) was performed due to a sibling with a similar clinical presentation. The analysis identified a heterozygous c.229 C>G (p.Leu77Val) missense variant in the ATAD3A gene along with a 0.61 kb heterozygous deletion encompassing exons 3–4 of the same gene. The ATAD3A (NM_001170535.3: c.229C>G; p.Leu77Val) variant has a reported allele frequency of 0.00045 in 1,461,700 control chromosomes in the gnomAD exome database, including four homozygotes. However, despite this relatively high population frequency, experimental evidence from at least one study suggests that this variant impairs protein function, resulting in a partial loss-of-function (hypomorphic) effect, as demonstrated in a Drosophila model system [4]. This variant represents a hypomorphic allele and classified as likely pathogenic according to ACMG criteria and will only cause disease when in trans with another pathogenic null variant but will not cause disease in homozygous state [1]. Sanger sequencing confirmed that patient and her mother carry the heterozygous c.229C>G variant. The second variant in the ATAD3A gene, a heterozygous intragenic deletion of exons 3–4 identified through CNV analysis of the WES data (seq[GRCh38]1p36.33(1517167–1517775)x1). Although this heterozygous in-frame deletion could not be confirmed using a second method, as the deletion is too small to be detected by microarray analysis, it was reported in two different study performing long-range PCR and breakpoint junction analysis, respectively [1, 4]. We presumed that ATAD3A exon 3–4 heterozygous deletion, identified by WES-based CNV analysis, was inherited from the father.

The patient was subsequently diagnosed with PHRINL syndrome. As she was admitted to another hospital due to seizures, detailed information regarding the seizure type and treatment was unavailable. Despite medical management, she died from intractable seizures at the 8 months of age while receiving intensive care.

The parents of two affected neonates and a healthy son received genetic counseling regarding future pregnancies. Since PHRINL syndrome is inherited in an autosomal recessive manner, they were informed of the 25% recurrence risk of having affected children. The options of prenatal diagnosis by exome sequencing and preimplantation genetic testing for monogenic disorders were discussed.

Discussion

PHRINL syndrome should be considered in the differential diagnosis of hereditary metabolic disorders presenting with infantile cataracts, hypertrophic cardiomyopathy, and hypotonia. In the literature, increased urinary excretion of 3-methylglutaconic acid has been reported in cases harboring a heterozygous c.229 C>G missense variant in the ATAD3A gene in combination with a heterozygous deletion of exons 3–4 [1]. Although no lactic acidosis was detected on blood gas analysis and no abnormal metabolite excretion suggestive of mitochondrial disease was found on urine organic acid analysis in our patient, PHRINL syndrome should still be considered in the differential diagnosis of cases presenting with infantile cataracts, hypertrophic cardiomyopathy, and hypotonia.

Skopkova et al. [1] reported four cases from two unrelated families, all carrying the same genetic alterations as our patient, namely a heterozygous c.229C>G missense variant and a heterozygous deletion of exons 3–4 in the ATAD3A gene. In their series, all patients died between 13 and 20 months of age. In contrast, our patient died at 8 months of age, and a sibling suspected of carrying the same variants died at 9 months without a definitive diagnosis [1].

In the study by Skopkova et al. [1], patients exhibited intermittent elevations in lactate levels and increased urinary excretion of 3-methylglutaconic acid. However, these findings were not observed in our case, which may be explained by the lack of repeated blood and urine measurements.

Furthermore, Skopkova et al. [1] noted that patients with identical variants tend to exhibit similar phenotypes, suggesting a potential genotype-phenotype correlation and prognostic relevance. Consistent with these observations, our patient demonstrated a clinical phenotype comparable to previously reported cases. To our knowledge, this is the second report describing the coexistence of these two variants [1]. Table 1 presents the clinical findings of all cases in the literature with the c.229C>G heterozygous missense variant and a heterozygous deletion of exons 3–4 in the ATAD3A gene [1].

Table 1.

Clinical findings of all 5 cases reported in the literature (first 4 patients are from the study by Skopkova et al. [1] last patient is from this study)

Patient	Gender	Hypotonia	Cataract	Cardiomyopathy	Seizure	Life span
Family 1 patient 1	Male	1 month	5 months	7 months	8 months	13 months
Family 1 patient 2	Male	3 months	3 months	11 months	11 months	15 months
Family 2 patient 3	Male	3 months	3 months	None	N/A	20 months
Family 2 patient 4	Male	3 months	3 months	N/A	N/A	17 months
Current study	Female	3 months	4 months	None	8 months	8 months

N/A, not available.

Congenital cataract is a key diagnostic clue in hereditary metabolic disorders and is associated with a wide range of conditions, including galactosemia, peroxisomal disorders, lysosomal storage diseases, and mitochondrial disorders [5]. In ATAD3A-related disease, it often represents an early clinical feature, although the underlying pathophysiological mechanism remains unclear [6]. In our case, both the patient and the deceased sibling had a history of cataract surgery. These findings suggest that ATAD3A mutations should be considered in the differential diagnosis of hereditary metabolic disorders presenting with congenital cataracts.

In mitochondrial diseases, impaired oxidative phosphorylation leads to insufficient ATP production to meet the high energy demands of cardiac muscle. Consequently, cardiac contractility is impaired, leading to compensatory hypertrophy [7]. Hypertrophic cardiomyopathy is the most common manifestation of Pompe disease in infancy [7]. In this context, the presence of additional findings such as cataracts and hypotonia should raise suspicion of PHRINL syndrome. Table 2 summarizes inherited metabolic disorders that present with at least two of the following findings: hypotonia, cataract, and cardiomyopathy. In our case, hypertrophic cardiomyopathy had not developed by 8 months of age. In contrast, it was detected in the patient's sibling, who was presumed to have the same condition, at 7 months. Previous reports indicate that hypotonia and cataracts may present in the first month of life, with cardiomyopathy emerging later [1]. Unlike other PCH subtypes, congenital cataracts and hypertrophic cardiomyopathy are consistently reported in ATAD3A-related PHRINL cases, and serve as key distinguishing features. Cataract is a rare but recurring manifestation in ATAD3A deficiency, whereas it is virtually absent in classic PCH subtypes [2]. Similarly, hypertrophic cardiomyopathy represents a hallmark of mitochondrial dysfunction associated with ATAD3A variants and may further aid in differentiation in infants with hypotonia and cerebellar atrophy [8]. Taken together, the coexistence of ocular and cardiac findings provides strong diagnostic clues to differentiate PHRINL from other forms of PCH [2, 8].

Table 2.

Inherited metabolic disorders presenting with at least two of the following findings: hypotonia, cataract, and cardiomyopathy [9]

​	Disease	OMIM	Gene	Inheritance	Specific metabolite	Cataract	Hypotonia	Hypertrophic cardiomyopathy	Other clinical manifestations of associated metabolic disorders
Mitochondrial disorders	Sengers syndrome	212350	AGK	AR	3-methylglutaconic acid in urine	Yes	Yes	Yes	Exercise intolerance
					Lactic acidosis				Normal mental development
	TMEM70 defect	614052	TMEM70	AR	Lactic acidosis	No	Yes	Yes	Neurological regression
Trafficking disorders	Vici syndrome	242840	EPG5	AR	–	Yes	Yes	Yes	Corpus callosum agenesis
									Cutaneous albinism
									Immune dysfunction
	Barth syndrome	302060	TAZ	XLR	Neutropenia	No	Yes	Yes (rare)	Skeletal muscle weakness
					3-methylglutaconic aciduria				Growth retardation
					Hypocholesterolaemia
	Mucolipidosis type IV	252650	MCOLN1	AR	​	Yes	Yes	No	Intellectual disability
									Limited or absent speech
									Difficulty chewing and swallowing
	Lowe syndrome	309000	OCRL1	XLR	Aminoaciduria	Yes	Yes	No	Renal Fanconi syndrome
Lysosomal disorders	Multiple sulfatase deficiency	272200	SUMF1	AR	Urine GAG	Yes	Yes	No	Coarse face, skeletal dysplasia
									Neurodegeneration
					Enzyme analysis				Ichthyosis
									Hepatosplenomegaly
Small molecule disorders	ITPase deficiency	616647	ITPA	AR	–	Yes	No	Yes	Early infantile encephalopathy
									Seizures
									Severe developmental delays
Glycogen storage disorders	Pompe disease	232300	GAA	AR	GAA enzyme activity	No	Yes	Yes	Macroglossia
					Urine tetrasaccharide				Hepatomegaly
									Progressive muscle weakness
	Danon disease	300257	LAMP2	XLD	High CK	No	Yes	Yes	Mental retardation
									Retinopathy
Fatty acid oxidation disorder	VLCAD deficiency	201475	ACADVL	AR	Plasma acylcarnitines (C14:1)	No	Yes	Yes	Hypoketotic hypoglycaemia
									Rhabdomyolysis
	LCHAD/TFP deficiency	609016/620300	HADHA/HADHB	AR/AR	Urine 3-OH-dicarboxylic acids	No	Yes	Yes	Retinopathy
									Peripheral neuropathy
	MADD	231680	ETFA/ETFB/ETFDH	AR	Plasma acylcarnitines (C4-C18)	No	Yes	Yes	Encephalopathy
									Liver dysfunction
Peroxisomal disorders	Zellweger spectrum	​	PEX1-…-12	AR, AD	Plasma VLCFA, phytanic acid	Yes	Yes	No	Facial dysmorphism
									Seizures
									Liver dysfunction
									Cortical renal cysts
Disorders of amino acid metabolism	Glutaminase hyperactivity	618339	GLS	AD	High brain glutamate	Yes	Yes	No	Profound developmental delay
									Self-injurious behavior

AR, autosomal recessive; AD, autosomal dominant; XLR, X-linked recessive; XLD, X-linked dominant.

PCH comprises a heterogeneous group of neurodevelopmental disorders characterized by congenital reduction of pontine and cerebellar volumes, resulting in developmental delay and progressive neurodegeneration. Its ethology includes intrauterine infections, toxic or hypoxic-ischemic injury, metabolic disturbances, and diverse genetic defects. Advances in molecular diagnostics have led to the identification of more than 26 subtypes [10]. Clinically, PCH typically presents with prenatal onset, marked neonatal hypotonia, global developmental delay, pharmacoresistant epilepsy, extrapyramidal signs, neuropathy, and abnormal ocular motor function. The ATAD3A-related case presented here demonstrated normal development during the first 2 months of life, followed by the onset of hypotonia in the third month and a neurodegenerative course consistent with other PCH forms. PCH type 6, caused by autosomal recessive pathogenic variants in RARS2, is a mitochondrial encephalopathy characterized by neonatal lactic acidosis, severe encephalopathy, refractory seizures, hypotonia, spastic quadriplegia, microcephaly, and feeding difficulties. Its biochemical profile, marked by OXPHOS dysfunction and elevated lactate in serum and cerebrospinal fluid, confers partial overlap with PHRINL syndrome; however, the absence of cataracts and hypertrophic cardiomyopathy distinguishes RARS2-related disease from PHRINL [4].

Conclusion

The limited number of PHRINL syndrome cases in the literature underscores the importance of this report. PHRINL syndrome should be considered in infants with cataracts and cardiomyopathy, even when lactate levels and urinary excretion of 3-methylgluconate and 3-methylglutarate are normal.

Acknowledgments

ChatGPT 5.2 was used for checking and correcting the grammar of the manuscript.

Statement of Ethics

Ethical approval was not required for this study in accordance with local/national guidelines. Written informed consent was obtained from the parent/legal guardian of the patient for publication of the details of their medical case and any accompanying images. The CARE checklist has been completed by the authors and is attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000551787).

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

A.G. contributed to the study conception and design. Material preparation and data collection were performed by A.G., A.D., İ.M.T., and B.K. The draft of the manuscript was written by A.G., A.D., İ.M.T., and B.K., and other authors commented on the manuscript. All authors read and approved the final manuscript.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

All data supporting the findings of this study are available within the paper.