Beyond Typical Ataxia Telangiectasia: How to Identify the Ataxia Telangiectasia‐Like Disorders

Abstract

Background

Ataxia telangiectasia is one of the most common causes of autosomal recessive cerebellar ataxias. However, absence of telangiectasia, normal levels of alpha‐fetoprotein and negative genetic test may direct to alternative diagnosis with similar phenotypes such as ataxia telangiectasia‐like disorders (ATLD).

Cases

We report two instructive cases of ATLD: the first case with ataxia telangiectasia‐like disorder type 1 related to MRE11A gene, and the second case with ataxia telangiectasia‐like disorder type 2 related to PCNA gene.

Literature Review

ATLD is an unusual group of autosomal recessive diseases that share some clinical features and pathophysiological mechanisms with ataxia telangiectasia (AT). ATLD may be associated with mutations in the MRE11A (ATLD type 1) and PCNA (ATLD type 2) genes. ATLD belongs to the group of chromosomal instability syndromes. The reason for the term ATLD is related to the similar pathophysiological mechanisms observed in AT, which is characterized by chromosomal instability and radiosensitivity.

Conclusions

In this review, the main clinical features, biomarkers, brain imaging and genetics of ATLD are discussed. Mutations in the MRE11A and PCNA genes should be included in the differential diagnosis for early onset cerebellar ataxia with absence of telangiectasia and normal levels of alpha‐fetoprotein.

View Supplementary Video 1

Ataxia telangiectasia (AT) is a multisystem degenerative genetic disease with early onset ataxia. Typical clinical features of AT include progressive cerebellar ataxia, telangiectasia, choreoathetosis and oculomotor apraxia. The disease has an autosomal recessive inheritance and is caused by mutations in the ATM gene located on chromosome 11q22.3–23.1. ¹ Variable and atypical phenotypes may occur, with late‐onset ataxia or pure dystonia, and absence of telangiectasia. Other features usually observed in AT are malignancy susceptibility, recurrent sinus and lung infections secondary to immunodeficiency, genomic instability, sensitivity to ionizing radiation and increased serum levels of alpha‐fetoprotein. ² , ³

Although advances in next‐generation sequencing technologies have allowed the genetic diagnosis of atypical cases of AT, some ATM‐negative patients with early onset ataxia have been related to new genes and determined as ataxia telangiectasia‐like disorders (ATLD). The term ATLD is associated with two unusual genetic diseases: ATLD1 related to mutations in MRE11A gene, and ATLD2 which is related to PCNA gene mutations. ⁴ , ⁵

In this article, we report two instructive cases that presented with early onset ataxia and negative investigation for AT, and whose additional investigation confirmed ATLD: two siblings with MRE11A gene mutations causing ATLD1, and one patient with PCNA gene mutations causing ATLD2. Furthermore, the main clinical features, pathophysiological mechanisms, biomarkers, neuroimaging, genetics and differential diagnosis of ATLD are discussed.

A literature search was performed following the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines in both MEDLINE and LILACS databases using “ataxia telangiectasia‐like disorders”, “ataxia telangiectasia like disorders”, “ataxia telangiectasia‐like”, “ataxia telangiectasia”, “MRE11A gene”, “ATLD1”, “PCNA gene”, “ATLD2”, etc. in the medical subject headings, title, abstract, or author‐supplied keywords. Original articles, reviews or case reports were included. Only cases with confirmed diagnosis were analyzed. In total, we found around 7000 results, and those were filtered by the authors. Sixteen case reports of ATLD, including a total of 42 patients, were found in our literature review. Thirty eight patients had ATLD1, while 4 patients had ATLD2.

Case Series

In order to better illustrate ATLD, we describe below two instructive cases: two siblings with ATLD1 and one patient of ATLD2.

Case 1

An 8‐year‐old girl presented with slow progression of gait ataxia that started at 2 years. Parents were non‐consanguineous. Neurological examination showed global ataxia, hypotonia, choreoathetosis, abnormal eye movements (oculomotor apraxia and slow saccades), mild dystonia in hands and feet, absence deep tendon reflexes and distal amyotrophy (Video S1 ‐ part 1). Vitamin E, alpha‐fetoprotein and albumin were normal. Brain magnetic resonance imaging (MRI) was normal (Figure 1). Electromyography (EMG) showed axonal neuropathy. Whole exome sequencing (WES) identified two heterozygous variants in the MRE11A gene NM_005590.4(MRE11):c.1876_1895dup (p.Lys633fs) and NM_005590.4(MRE11):c.1516G > T (p.Glu506Ter). Both variants were previously described as pathogenic mutations related to ATLD1, which confirmed the diagnosis. Her sibling, a 5‐year‐old boy, presented with progressive gait ataxia since 2‐years‐old, and genetic testing disclosed the same mutations reported in the proband.

Figure 1.

Patient with ataxia telangiectasia‐like disorder type 1 (ATLD1) with MRE11A gene mutations, presenting with normal cerebellar volume on brain magnetic resonance imaging (A to C).

Case 2

An 11‐year‐old girl presented with slow progressive ataxia since 3‐years‐old. There were also mild cognitive dysfunction and hearing loss. Parents were non‐consanguineous. Neurological examination showed global ataxia, slurred speech, mild oculomotor apraxia and reduced deep tendon reflexes without atrophic muscle or peripheral sensibility alteration (Video S1 ‐ part 2). EMG was normal. Subtle and isolated telangiectasias were observed in the shoulders, back, face and limbs (Figure 2 ). Serum levels of immunoglobulins (IgA and IgG) were decreased. Inborn error of metabolism screening and alpha‐fetoprotein level were normal. Audiometry showed sensorineural hearing loss. Brain MRI and EMG were normal (Figure 2). The presence of early onset cerebellar ataxia associated with immunodeficiency and telangiectasias suggested AT. However, alpha‐fetoprotein was normal. WES was performed and disclosed pathogenic mutations in the PCNA gene NM_002592.2(PCNA):c.443G > C(p.Cys148Ser), and confirmed ATLD2.

Figure 2.

Patient with ataxia telangiectasia‐like disorder type 2 (ATLD2) with PCNA gene mutations, presenting with normal cerebellar volume on brain magnetic resonance imaging (A to C). Note mild conjunctival (D) and skin telangiectasia (E).

Literature Review

Classification and Concepts

ATLD are rare autosomal recessive disorders included in the group of chromosomal instability syndromes. The clinical features are characterized by progressive cerebellar degeneration and ionizing radiation hypersensitivity, similar to AT. ⁶ , ⁷ Different mutations, either in homozygosis or compound heterozygosis, in two different genes have been identified and directly related to the specifics subtypes of ATLD. ¹ As aforementioned, ATLD are divided into two subtypes: ATLD1 is caused by MER11A gene mutations, located on chromosome 11q21, while ATLD2 is caused by PCNA gene mutations, located on chromosome 20p12. ⁸

Clinical Features

The classical phenotype of AT is characterized by early onset cerebellar ataxia, telangiectasia and immunodeficiency. ⁹ Ataxia usually develops in childhood, before 4‐years‐old. ¹⁰ Cutaneous telangiectasia, which is a hallmark, may appear later, around 8–10 years, or hardly ever may be absent. ³ , ¹¹ Other features include malignancy susceptibility, genomic instability, sensitivity to ionizing radiation, increased levels of alpha‐fetoprotein and recurrent infections. ¹ , ² , ³ Around 20% of AT patients develop some malignancy, and the most frequent are lymphoma and leukemia. ¹² , ¹³ Some atypical forms of AT may present with late onset ataxia with no telangiectasia or pure dystonia. ¹

During the course of the AT, movement disorders may be observed: myoclonus (92%), dystonia (89%), choreoathetosis (89%), tremor (74%) and parkinsonism (41%). ¹⁴ Neuropathy may occur, particularly in long disease duration. ¹⁰ Cognitive impairment, but not severe dementia or encephalopathy, may occur as a late manifestation, usually around 10‐years‐old. ¹⁵ Wheelchair is frequently necessary in the second decade of life. ¹⁶ Delayed pubertal development, growth retardation, insulin‐resistant diabetes and occasionally hepatic dysfunction may be found in AT. ¹¹ , ¹⁵ , ¹⁷ Death may occur in the third decade of life due to malignancy complications or aspiration pneumonia. ¹⁸

The clinical features of ATLD resemble AT, since it includes cerebellar ataxia, movement disorders and radiosensitivity. ⁶ On the other hand, ATLD usually have a later onset, slower progression and milder phenotypes. Moreover, telangiectasia, immunodeficiency and increased alpha‐fetoprotein are rarely observed in ATLD. ⁷ , ¹⁹

Clinical features of ATLD1 are characterized by cerebellar ataxia, eye movement abnormalities, radiosensitivity, choreoathetosis and dystonia. ²⁰ Rarely, short stature, microcephaly, cognitive impairment, facial dyskinesia and neuropathy may be found in ATLD1. ²⁰ The most common oculomotor abnormalities in ATLD1 are slow and dysmetric saccades, oculomotor apraxia, delayed convergence and gaze‐evoked nystagmus. ¹⁹ , ²⁰ , ²¹ , ²²

ATLD2 was firstly described in 2014, although function in DNA repair and replication of the PCNA gene is known since 1986. ⁴ Clinical features of ATLD2 include cerebellar ataxia, short stature, hearing loss, premature aging, telangiectasia and photosensitivity. ⁴ Other clinical signs include intellectual impairment, foot deformity, speech and swallowing difficulties, and muscle weakness. ⁵ , ²³ Oculomotor abnormalities have not been described in the few reports, but our patient had mild oculomotor apraxia. In opposite to AT, risk for malignancy appears to be low in ATLD: lung adenocarcinoma was reported in ATLD1, and sunlight‐induced skin cancer in ATLD2. ⁴ , ¹⁵ , ¹⁶

Pathophysiological Mechanisms and Genetics

Human DNA is constantly exposed to endogenous and exogenous mutagenic stimuli, that produces diverse lesions. ²⁴ , ²⁵ DNA damage response (DDR) is a particular way of the DNA repair mechanism involved in lesions detection, signaling, and repair promotion as well as cell cycle progression control. ²⁶ Changes in DDR shows DNA damage and subsequent genomic instability, cell cycle deregulation that ensues overgrowth and cellular apoptosis. ²⁴ Dysfunction of DDR is a remarkable feature in pathophysiological mechanisms of the chromosome instability syndromes.

The function of the Mre11 protein is biochemically linked to ATM, which is a critical component of the cellular response to DDR. ²⁴ The Mre11 protein is a component of the Mre11/Rad50/Nbs1 (MRN) complex, which is involved in different responses to cellular damage induced by ionizing radiation and radiomimetic chemicals. ²⁷ It is suggested that MRN complex, particularly Mre11, may be required for full ATM activation, which may also provide an explanation for the phenotypic similarity between ATLD1 and AT. ³ , ⁵ , ¹⁸ , ²⁷

Although the mechanism by which MRE11 gene mutations give rise to cerebellar ataxia or microcephaly is unclear, and it is possible that NBN and RAD50 genes are required to protect against the development of microcephaly, but are insufficient to prevent cerebellar atrophy. ²⁵ Therefore, microcephaly is uncommon in ATLD1 and a key feature in the Nijmegen breakage syndrome. Mutations in the RAD50 gene have been associated with Nijmegen breakage syndrome‐like disorder. ²⁸

The majority of variants in ATLD1 are related to missense, nonsense or splicing mutations. Some of them may not change translated amino acids but affect protein efficiency. ²³

As for ATLD2, repair synthesis and replication are dependent on the DNA polymerase accessory protein proliferating cell nuclear antigen. ²⁹ As it plays an important role in DNA replication, PCNA gene is highly conserved throughout evolution. ⁵ PCNA interacts with a large number of accessory proteins and acts as a platform to coordinate the multiple enzymatic activities. ³⁰ The major cellular role of this protein is to recruit and retain the replicative DNA polymerases at the sites of DNA synthesis during DNA replication. It forms a homotrimeric ring encircling and freely sliding along the DNA helix. ⁵ All reported mutations in the PCNA gene are a missense.

Imaging, Neurophysiology and Biomarkers

There are few data about neuroimaging features that may differentiate AT, ATLD1 and ATLD2. Brain MRI in AT usually shows cerebellar atrophy. Furthermore, AT patients may present with white matter hypointensity lesions in T2‐weighted images (SWI), suggesting that hemosiderin deposit related to telangiectatic vessels. ³¹ These findings have not been described in ATLD.

Brain MRI may be normal if performed in the early stages of the ATLD, as well as AT. This is relevant since ATLD should be included in the group of autosomal recessive ataxias with no cerebellar atrophy, together with Friedreich ataxia, ataxia related with vitamin E deficiency, Refsum disease and abetalipoproteinemia. In our cases, the patients presented with normal cerebellar volume. In case 2, despite 8 years of disease duration, there was no cerebellar atrophy. In spite of the normal MRI described in our patients, the majority of patients with ATLD present with cerebellar atrophy during the course of the disease, mainly in the cerebellar vermis. ⁵ , ²¹ , ²²

EMG and conduction studies may show axonal sensory or sensorimotor neuropathy in ATLD1. In opposite, peripheral neuropathy has not been described in ATLD2. ¹⁹ Cranial neuropathy characterized by sensorineural hearing loss is more frequent in ATLD2. ⁵ , ²³

Alpha‐fetoprotein, albumin, vitamin E, cholesterol and immunoglobulin serum levels are frequently used as biomarkers in the investigation of autosomal recessive cerebellar ataxias. AT usually present with high levels of alpha‐fetoprotein and low levels of immunoglobulins. Nonetheless, these biomarkers are rarely abnormal in ATLD patients. ⁴ , ⁵ , ⁶ , ¹⁹ , ²¹ , ³² Hypersegmented neutrophils in peripheral blood smear, that is known to be present in several conditions that affect DNA replication, are possible biomarkers for ATLD1. ³³ In Table 1 we describe the main differences between AT, ATLD1 and ATLD2 concerning clinical features, biomarkers, genetics, neuroimaging and pathophysiological mechanisms.

Table 1.

Comparison of the clinical features, biomarkers and brain imaging between ataxia telangiectasia (AT), ataxia telangiectasia‐like disorder type 1 (ATLD1) and ataxia telangiectasia‐like disorder type 2 (ATLD2)

Clinical Features	AT (ATM)	ATLD1 (MRE11A)	ATLD2 (PCNA)
Ataxia	+	+	+
Dysarthria	+	+	+
Telangiectasia	+	−	+
Eye movement disorders	+	+	−
Photophobia and photosensitivity	−	−	+
Movement disorders (choreoathetosis, dystonia, myoclonus, tremor)	+	+	−
Cognitive dysfunction	+	+*	+
Sensorineural hearing loss	−	−	+
Skin abnormalities	+	−	+
Microcephaly	−	−	+
Short stature, developmental delay	+	+*	+
Lymphoid tumors predisposition	+	−	Unknown
Recurrent infections	+	−	−
Increased levels of alpha‐fetoprotein	+	−	Unknown
Reduced levels of Immunoglobulin	+	−	−
Cerebellar atrophy	+	+	+*

AT, ataxia telangiectasia; ATLD1, ataxia telangiectasia‐like disorder type 1; ATLD2, ataxia telangiectasia‐like disorder type 2.

^* Poor evidence.

Other Chromosomal Instability Syndromes

Chromosomal instability syndromes are a group of diseases that results from mutations in genes involved in DDR pathway. ²⁵ , ²⁶ Similar to ATLD, other diseases that are included in the chromosomal instability syndromes are: AT, Fanconi anemia, Nijmegen breakage syndrome and Bloom syndrome. Chromosomal instability syndromes have an overlap in clinical features, immunodeficiency and/or malignancy predisposition. ³⁴

Despite similarities in the cellular defects displayed by cells derived from patients with chromosomal instability syndromes, the impact on the development and maintenance of specific tissues and organs can be strikingly different, particularly with respect to the nervous system. ²⁶ The underlying reason for this stark contrast in disease‐associated neuropathology and how it is related to specific repair deficiencies is not well understood. ²⁵

The clinical features of all the chromosome instability disorders are quite distinct, often enabling a highly probable diagnosis based on clinical signs, symptoms and routine laboratory testing. Desired diagnostic certainty can be achieved with genetic testing. ²⁵ In Table 2 the main clinical features present in each of the classical disorders of chromosomal instability syndrome.

Table 2.

Chromosomal instability syndromes: Clinical features, inheritance and related genes

Syndrome	Clinical Features	Inheritance	Gene
Nijmegen breakage syndrome	Microcephaly, lymphoreticular malignancies, short stature, hypersensitive to ionizing radiation, skin pigmentation, intellectual disability	Autosomal recessive	NBS1
Fanconi anemia	Bone marrow failure and susceptibility to cancer (mainly acute myeloid leukemia), mental retardation, kidneys, heart, and skeleton malformation, dysmorphic features, skin abnormalities	Autosomal recessive or X‐linked	FANC genes
Bloom syndrome	Photosensitivity, malignancy predisposition, immunodeficiency, mild mental retardation, telangiectasia in face, skin abnormalities	Autosomal recessive	BLM
Ataxia telangiectasia	Progressive early ataxia, cerebellar atrophy immunodeficiency, hypersensitive to ionizing radiation, malignancy predisposition, telangiectasia	Autosomal recessive	ATM
Ataxia telangiectasia‐like disorders (ATLD)	Progressive early ataxia, cerebellar atrophy, short stature, developmental delay, telangiectasia, deafness	Autosomal recessive	MRE11A (ATLD1) PCNA (ATLD2)

Differential Diagnosis for the Ataxia Telangiectasia‐Like Disorders

Given the rarity of the ATLD and their inherent clinical complexity, to establish a specific diagnosis can be a challenging for all clinicians. Several neurological disorders that also occur with early ataxia in childhood associated with multisystemic impairment, beyond AT, should be ruled out with step by step approach to establish the specific diagnosis.

The Nijmegen breakage syndrome, also called as ataxia‐telangiectasia variant V1 (AT‐V1), is a differential diagnosis, and microcephaly is a clue to support this disorder. ³⁵ The following diseases: congenital ocular motor apraxia type Cogan (COMA), congenital ataxias with cerebellar hypoplasia, early onset Friedreich ataxia, ataxia with vitamin E deficiency, abetalipoproteinemia, Coq10 deficiency, Cockayne disease, ataxia with oculomotor apraxia type 1 and 2, infantile onset spinocerebellar ataxia (IOSCA), Refsum disease, ataxia with mutations in Polymerase Gamma (POLG gene), spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1), autosomal recessive ataxia of Charlevoix‐Saguenay (ARSACS), Marinesco‐Sjögren syndrome, leukodystrophies with early onset ataxia, neuronal ceroid lipofuscinosis, may present with overlapping features with ATLD. The clinical distinction between these diseases is difficult. Progression and course of the disease, neurological examination and serum biomarkers are the keystone in the diagnostic approach. Commonly, a genetic study or protein assessment is necessary. In Table 3 the differential diagnosis for ATLD and the most relevant clinical hallmarks for each disease are summarized.

Table 3.

Summary of the main differential diagnosis for ATLD and the most relevant clinical hallmarks for each disease

Disease	Main Clinical Features	Clinical Hallmarks
Congenital ocular motor apraxia type Cogan (COMA)	Ocular motor apraxia since birth, ataxia (mostly truncal), non‐progressive	Early ocular motor apraxia
Congenital ataxias	Developmental delay, non‐progressive course, hypotonia followed by ataxia, language disorders and intellectual disability	Cerebellar hypoplasia, pontocerebellar hypoplasia, cerebellar malformation, dysmorphic features associated with specific syndromes
Early onset Friedreich ataxia	Early progressive ataxia, absent lower limb tendon reflex, impaired proprioception and vibratory sense, Babinski sign	Scoliosis, diabetes, pes cavus, hypertrophic cardiomyopathy, no cerebellar atrophy on brain MRI
Ataxia with vitamin E deficiency	Early progressive ataxia, proprioception loss	Low level of serum vitamin E, no cerebellar atrophy on brain MRI
Abetalipoproteinemia	Ataxia, pigmentary degeneration of the retina, malabsorption syndrome	Acanthocytosis
Refsum disease	Ataxia, retinitis pigmentosa, peripheral neuropathy, deafness	Elevated protein level in CSF, high serum levels of phytanic acid
Ataxia with oculomotor apraxia type 1 and 2	Ataxia, oculomotor apraxia, movement disorders, cerebellar atrophy, peripheral neuropathy	Hipoalbuminemia, hypercolesterolemia, high serum levels of serum alpha‐fetoprotein
Charlevoix‐Saguenay (ARSACS)	Early onset progressive ataxia, spasticity, peripheral neuropathy	Hipermyelinated retinal fibers, MRI with hypotensity in pons
Infantile onset spinocerebellar ataxia (IOSCA)	Ataxia, ophthalmoplegia, hearing loss, seizures, sensory axonal neuropathy	Abnormal liver enzimes (rare)
Coenzime Q10 deficiency	Ataxia, seizures, myopathy	Decreased levels of coenzyme Q10 in muscle biopsy
Cockayne syndrome	Growth deficiency, microcephaly, sensorial hearing loss, pigmentary retinopathy, ataxia, peripheral neuropathy, mental retardation	Premature aging, photosensitivity, basal ganglia calcification
POLG gene mutations	Ataxia, epilepsy, myopathy, axonal neuropathy, hypogonadism, liver failure	Progressive external ophthalmoplegia
Marinesco‐Sjögren syndrome	Ataxia, myopathy, short stature, hypergonadotropic hypogonadism	Congenital cataracts, increased serum creatine kinase
Leukodystrophy	Ataxia and other movement disorders, spasticity, bulbar symptoms, visual loss, neuropathy, behavioral changes	Withe matter abnormalities on brain MRI
Neuronal ceroid lipofuscinosis	Ataxia and others movement disorders, encephalopathy, seizures, visual loss, language delay	Rapid neurologic regression, abnormalities on EEG

Therapeutic Approaches

Patients with ATLD may present with variable degrees of disease progression and different complications. Despite the lack of a disease‐modifying therapy, early diagnosis allows genetic counseling, symptomatic treatment and rehabilitation programs. Patients with ATLD should be followed by an experienced multidisciplinary team of healthcare professionals. ¹⁰ Occupational therapy, speech therapies, nutritional support and motor physiotherapy are essential.

The management and treatment of ATLD is symptomatic and supportive. Some drugs may be useful in the management of symptoms. Botulinum toxin is the first‐choice treatment for focal dystonia. ¹⁰ , ³⁶ , ³⁷ Some studies have showed improvement of dystonia with the use of levodopa in both, ATLD and AT. ²⁰ , ³⁸ Oral drugs therapy with anticholinergic drugs (eg biperiden and trihexyphenidyl) ¹⁰ , ³⁷ and GABA (c‐aminobutyric acid) mimetics (eg baclofen, clonazepam) may alleviate symptoms in patients with generalized dystonia, blepharospasm, pain and oromandibular dystonia. ³⁹ Since ATLD and AT patients are radio‐sensitive, X‐ray exposure and radiotherapy must be avoid. ¹⁰ , ⁴⁰

The monitoring of immunological condition, whole routine evaluation of immunizations, screened for malignancies and endocrine abnormalities should be performed periodically in ATLD patients. ¹⁰

Conclusions

Recessive cerebellar ataxia in childhood comprises a heterogeneous and complex group of the diseases, and frequently etiological diagnosis is a challenge. AT is one of the most frequent causes, but absence of telangiectasia, normal levels of alpha‐fetoprotein and negative genetic test may direct to alternative diagnosis with similar phenotypes. Taking into account the advances in the neurogenetic field, patients with atypical phenotypes of AT have been associated with newer mutations. In line with this, mutations in the MRE11A (ATLD1) and PCNA (ATLD2) genes should be included in the differential diagnosis for early onset cerebellar ataxias with absence of telangiectasia and normal levels of alpha‐fetoprotein. The term ATLD is related to the similarity of pathophysiological mechanisms observed in AT, which is characterized by chromosomal instability and radiosensitivity. WES is paramount to detect the new gene mutations related to ATLD1 and ATLD2.

Author Roles

(1) Patients Evaluation: A. Conception, B. Organization, C. Execution; (2) Brain Imaging: A. Conception, B. Execution; (3) Manuscript: A. Writing of the first draft, B. Review, and Critique.

I.R.R.: 1A, 1B, 1C, 2A, 3A

P.C.A.A.P.M.: 1A, 1B, 1C, 2A, 3A

V.C.C.: 1A, 1B, 1C, 2A, 2B, 3A

K.H.D.: 1B, 1C, 2A, 3A

A.B.R.R.: 1B, 1C, 2A, 3A

J.H.A.: 1B, 1C, 2A, 3A

C.S.A.: 1B, 1C, 2A, 3A

O.G.P.B.: 1A, 1B, 1C, 3B

J.L.P.: 1A, 1B, 1C, 2A, 2B, 3A, 3B

Disclosures

Ethical Compliance Statement

he authors confirm that the approval of an institutional review board was not required for this work. We confirm that patient consent has been sought and allowed for this case and its publication. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest

The authors have no conflicts of interest to report and there was no funding for this work.

Financial Disclosures for the Previous 12 Months

The authors have no disclosures to report.

Supporting information

Video S1. Part 1: Patient with ataxia telangiectasia‐like disorder type 1 (ATLD1) with MRE11A gene mutations, presenting with ataxia, choroathetosis, oculomotor apraxia, and dystonia. Part 2: Patient with ataxia telangiectasia‐like disorder type 2 (ATLD2) with PCNA gene mutations, presenting with gait ataxia and mild oculomotor apraxia.